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    Iodine Storage and Metabolism of Mild to Moderate Iodine-Deficient Pregnant Rats. Sun Xin,Lu Li,Shan Ling,Shan Zhongyan,Teng Weiping Thyroid : official journal of the American Thyroid Association BACKGROUND:Severe iodine deficiency during pregnancy results in neurodevelopmental disorders in children, while the consequences of mild to moderate iodine deficiency (MMID) are uncertain. The concentration of iodine in the thyroid is the most accurate indicator of iodine nutrition. This study aimed to evaluate whether the iodine stores in the thyroid cover the needs of the mother and the fetus in iodine-sufficient and MMID conditions by inductively coupled plasma-mass spectrometry. METHODS:One hundred four-week-old female Wistar rats were randomly divided into MMID (low iodine intake [L]) and normal (normal iodine intake [N]) groups. The rats were fed for the next three months, and after pregnancy they were further divided into two subgroups, respectively: low iodine pregnancy (LP) and low iodine pregnancy with iodine supplement (LP+), and normal iodine intake pregnancy (NP) and normal iodine intake pregnancy with iodine supplement (NP+). The iodine intake of pregnant rats in the NP+ and LP+ groups was twice as much as in the NP and LP groups. The rats were sacrificed on gestational day 15 and postnatal day 7. The iodine concentration in the thyroid of the maternal and newborn rats, maternal serum, placenta, and amniotic fluid were determined by inductively coupled plasma-mass spectrometry. RESULTS:The concentration of iodine in the thyroid of the N group was significantly higher than that in the L group before pregnancy. The concentration of iodine in the maternal thyroids of the LP group decreased during pregnancy, whereas that of the NP group did not change significantly. There was no significant difference in the iodine concentration in the thyroid of mothers and offspring between the NP and NP+ groups, but it was significant between LP and LP+ groups. The concentration of iodine in amniotic fluid was significantly different between the four groups. CONCLUSION:There is sufficient iodine storage in the thyroid of maternal rats with normal iodine intake during pregnancy, and there is no need for iodine supplementation. However, iodine stores are insufficient in rats with MMID. Iodine supplementation can increase the iodine concentration in the thyroid of maternal rats with MMID and their offspring, as well as in the amniotic fluid during pregnancy. 10.1089/thy.2016.0611
    Elevated fetal steroidogenic activity in autism. Baron-Cohen S,Auyeung B,Nørgaard-Pedersen B,Hougaard D M,Abdallah M W,Melgaard L,Cohen A S,Chakrabarti B,Ruta L,Lombardo M V Molecular psychiatry Autism affects males more than females, giving rise to the idea that the influence of steroid hormones on early fetal brain development may be one important early biological risk factor. Utilizing the Danish Historic Birth Cohort and Danish Psychiatric Central Register, we identified all amniotic fluid samples of males born between 1993 and 1999 who later received ICD-10 (International Classification of Diseases, 10th Revision) diagnoses of autism, Asperger syndrome or PDD-NOS (pervasive developmental disorder not otherwise specified) (n=128) compared with matched typically developing controls. Concentration levels of Δ4 sex steroids (progesterone, 17α-hydroxy-progesterone, androstenedione and testosterone) and cortisol were measured with liquid chromatography tandem mass spectrometry. All hormones were positively associated with each other and principal component analysis confirmed that one generalized latent steroidogenic factor was driving much of the variation in the data. The autism group showed elevations across all hormones on this latent generalized steroidogenic factor (Cohen's d=0.37, P=0.0009) and this elevation was uniform across ICD-10 diagnostic label. These results provide the first direct evidence of elevated fetal steroidogenic activity in autism. Such elevations may be important as epigenetic fetal programming mechanisms and may interact with other important pathophysiological factors in autism. 10.1038/mp.2014.48
    Association of Folic Acid Supplementation During Pregnancy With the Risk of Autistic Traits in Children Exposed to Antiepileptic Drugs In Utero. Bjørk Marte,Riedel Bettina,Spigset Olav,Veiby Gyri,Kolstad Eivind,Daltveit Anne Kjersti,Gilhus Nils Erik JAMA neurology Importance:Strategies to prevent autism in children exposed to antiepileptic drugs (AEDs) during pregnancy are important. Objective:To explore whether folic acid supplementation and folate status in pregnancy are associated with reduced risk of autistic traits owing to in utero AED exposure. Design, Setting, and Participants:The population-based, prospective Norwegian Mother and Child Cohort Study approached Norwegian-speaking women attending routine ultrasonographic examinations from June 1999 through December 31, 2008 (163 844 of 277 702 women refused). No exclusion criteria were applied beyond language. Questionnaires during and after pregnancy, analysis of blood samples, and linkage to the Medical Birth Registry of Norway were performed. Children aged 18 to 36 months of women with available information on use of AEDs and of folic acid supplementation (n = 104 946) were included in the analysis from March 1, 2016, through June 13, 2017. Exposures:Maternal folic acid supplementation 4 weeks before to 12 weeks after conception. Plasma folate concentration was analyzed at gestational weeks 17 to 19. Main Outcomes and Measures:Autistic traits were evaluated using the Modified Checklist for Autism in Toddlers and Social Communication Questionnaire. Odds ratios (ORs) for autistic traits in children by maternal use vs nonuse of folic acid supplements were adjusted for maternal health and socioeconomic factors. Folate concentrations and folic acid doses were associated with the degree of autistic traits. Results:The overall mean (SD) age of the 104 946 mothers of participating children was 29.8 (4.6) years, with complete information available for analysis in 103 868. Mean (SD) age of women with epilepsy who received AED treatment was 29.4 (4.9); women with epilepsy who did not receive AED treatment, 29.1 (4.9); and without epilepsy, 29.8 (4.6) years. In the 335 children exposed to AEDs, the risk for autistic traits was significantly higher at 18 months of age (adjusted OR [AOR], 5.9; 95% CI, 2.2-15.8) and 36 months of age (AOR, 7.9; 95% CI, 2.5-24.9) when their mothers had not used folic acid supplements compared with children of mothers who had used supplements. Among women without epilepsy, the corresponding risks were lower at 18 months of age (AOR, 1.3; 95% CI, 1.2-1.4) and 36 months of age (AOR, 1.7; 95% CI, 1.5-1.9); among the 389 children of women with untreated epilepsy, the corresponding risks were not significant at 18 months of age (AOR, 1.0; 95% CI, 0.4-3.0) and 36 months of age (AOR, 2.5; 95% CI, 0.4-16.6). Degree of autistic traits was inversely associated with maternal plasma folate concentrations (β = -0.3; P = .03) and folic acid doses (β = -0.5; P < .001). Concentrations of AEDs were not associated with the degree of autistic traits. Conclusions and Relevance:Risk of autistic traits in children exposed to AEDs in utero may be mitigated by periconceptional folic acid supplementation and folate status. Fertile women using AEDs should take folic acid supplements continuously. 10.1001/jamaneurol.2017.3897
    Foetal oestrogens and autism. Baron-Cohen Simon,Tsompanidis Alexandros,Auyeung Bonnie,Nørgaard-Pedersen Bent,Hougaard David M,Abdallah Morsi,Cohen Arieh,Pohl Alexa Molecular psychiatry Elevated latent prenatal steroidogenic activity has been found in the amniotic fluid of autistic boys, based on measuring prenatal androgens and other steroid hormones. To date, it is unclear if other prenatal steroids also contribute to autism likelihood. Prenatal oestrogens need to be investigated, as they play a key role in synaptogenesis and corticogenesis during prenatal development, in both males and females. Here we test whether levels of prenatal oestriol, oestradiol, oestrone and oestrone sulphate in amniotic fluid are associated with autism, in the same Danish Historic Birth Cohort, in which prenatal androgens were measured, using univariate logistic regression (n = 98 cases, n = 177 controls). We also make a like-to-like comparison between the prenatal oestrogens and androgens. Oestradiol, oestrone, oestriol and progesterone each related to autism in univariate analyses after correction with false discovery rate. A comparison of standardised odds ratios showed that oestradiol, oestrone and progesterone had the largest effects on autism likelihood. These results for the first time show that prenatal oestrogens contribute to autism likelihood, extending the finding of elevated prenatal steroidogenic activity in autism. This likely affects sexual differentiation, brain development and function. 10.1038/s41380-019-0454-9
    Perinatal Phosphatidylcholine Supplementation and Early Childhood Behavior Problems: Evidence for CHRNA7 Moderation. Ross Randal G,Hunter Sharon K,Hoffman M Camille,McCarthy Lizbeth,Chambers Betsey M,Law Amanda J,Leonard Sherry,Zerbe Gary O,Freedman Robert The American journal of psychiatry OBJECTIVE:α7-Nicotinic receptors are involved in the final maturation of GABA inhibitory synapses before birth. Choline at levels found in the amniotic fluid is an agonist at α7-nicotinic receptors. The authors conducted a double-blind placebo-controlled trial to assess whether high-dose oral phosphatidylcholine supplementation during pregnancy to increase maternal amniotic fluid choline levels would enhance fetal development of cerebral inhibition and, as a result, decrease childhood behavior problems associated with later mental illness. METHOD:The authors previously reported that newborns in the phosphatidylcholine treatment group have increased suppression of the cerebral evoked response to repeated auditory stimuli. In this follow-up, they report parental assessments of the children's behavior at 40 months of age, using the Child Behavior Checklist. RESULTS:At 40 months, parent ratings of children in the phosphatidylcholine group (N=23) indicated fewer attention problems and less social withdrawal compared with the placebo group (N=26). The improvement is comparable in magnitude to similar deficits at this age associated with later schizophrenia. The children's behavior is moderated by CHRNA7 variants associated with later mental illness and is related to their enhanced cerebral inhibition as newborns. CONCLUSIONS:CHRNA7, the α7-nicotinic acetylcholine receptor gene, has been associated with schizophrenia, autism, and attention deficit hyperactivity disorder. Maternal phosphatidylcholine treatment may, by increasing activation of the α7-nicotinic acetylcholine receptor, alter the development of behavior problems in early childhood that can presage later mental illness. 10.1176/appi.ajp.2015.15091188
    Analysis of blood from Zika virus-infected fetuses: a prospective case series. Schaub Bruno,Vouga Manon,Najioullah Fatiha,Gueneret Michèle,Monthieux Alice,Harte Caroline,Muller Françoise,Jolivet Eugénie,Adenet Clara,Dreux Sophie,Leparc-Goffart Isabelle,Cesaire Raymond,Volumenie Jean-Luc,Baud David The Lancet. Infectious diseases BACKGROUND:Zika virus has spread through the Americas and the Caribbean since early 2015 and was rapidly declared a Public Health Emergency of International Concern by WHO because of the potential association with fetal anomalies. We analysed fetal and maternal fluids and tissues in fetuses with confirmed Zika virus infection prospectively monitored in Martinique, a French Caribbean island. METHODS:Since the beginning of the Zika virus outbreak in Martinique, all pregnant women undergo monthly fetal ultrasound examination surveillance. In this study, we prospectively studied all patients with fetal anomalies and a positive amniotic fluid for Zika virus by RT-PCR. Maternal and fetal blood, urine, amniotic fluid, placenta, and fetal tissues were tested for Zika virus by RT-PCR. Fetal blood was analysed to identify haematological and biological anomalies. FINDINGS:Between Jan 1, 2016, and Nov 10, 2016, we recruited eight cases of Zika virus infection. All but two cases were symptomatic during the first trimester. Fetal anomalies were only detected after 20 weeks' gestation. After an initial positive result, amniocentesis became negative in two cases and fetal blood was transiently Zika virus-positive in six cases. Fetal blood analyses showed a cholestatic pattern, anaemia, and infectious response. INTERPRETATION:Normalisation of amniotic fluid and fetal blood for Zika virus, as well as maternal blood and urine, shows the limitations of the performance of these investigations, due to the possibility of false negative results. Abnormal fetal blood needs to be investigated further to establish prognostic factors of severe Zika virus infections. FUNDING:None. 10.1016/S1473-3099(17)30102-0
    Combined liquid chromatography-tandem mass spectrometry analysis of progesterone metabolites. Sinreih Maša,Zukunft Sven,Sosič Izidor,Cesar Jožko,Gobec Stanislav,Adamski Jerzy,Lanišnik Rižner Tea PloS one Progesterone has a number of important functions throughout the human body. While the roles of progesterone are well known, the possible actions and implications of progesterone metabolites in different tissues remain to be determined. There is a growing body of evidence that these metabolites are not inactive, but can have significant biological effects, as anesthetics, anxiolytics and anticonvulsants. Furthermore, they can facilitate synthesis of myelin components in the peripheral nervous system, have effects on human pregnancy and onset of labour, and have a neuroprotective role. For a better understanding of the functions of progesterone metabolites, improved analytical methods are essential. We have developed a combined liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for detection and quantification of progesterone and 16 progesterone metabolites that has femtomolar sensitivity and good reproducibility in a single chromatographic run. MS/MS analyses were performed in positive mode and under constant electrospray ionization conditions. To increase the sensitivity, all of the transitions were recorded using the Scheduled MRM algorithm. This LC-MS/MS method requires small sample volumes and minimal sample preparation, and there is no need for derivatization. Here, we show the application of this method for evaluation of progesterone metabolism in the HES endometrial cell line. In HES cells, the metabolism of progesterone proceeds mainly to (20S)-20-hydroxy-pregn-4-ene-3-one, (20S)-20-hydroxy-5α-pregnane-3-one and (20S)-5α-pregnane-3α,20-diol. The investigation of possible biological effects of these metabolites on the endometrium is currently undergoing. 10.1371/journal.pone.0117984
    SWATH-Based Metabolomics of Follicular Fluid in Patients Shows That Progesterone Adversely Affects Oocyte Quality. Sun Zhengao,Song Jingyan,Zhang Xingxing,Wang Aijuan,Guo Ying,Yang Yi,Wang Xiaoming,Xu Kaiyue,Deng Jifeng BioMed research international Objective:We reveal the relationship between progesterone level in follicular fluid and oocyte quality based on sequential window acquisition of all theoretical fragment-ion spectra (SWATH™), a powerful high-resolution mass spectrometric data independent acquisition technique. Method:Follicular fluid samples were collected from 22 subjects (the level of progesterone > 1.5 ng/mL) of progesterone group, as well as from 22 subjects (the level of progesterone < 1.5 ng/mL) of control group, and analyzed using UPLC-Q-TOF. All methods were performed in accordance with ISO 9001:2008. Novel SWATH acquisition mode on an ultra-high performance liquid chromatography coupled with hybrid triple quadrupole time-of-flight mass spectrometry (with resolving power 20,000-40,000) was investigated for the analysis of human follicular fluid. The principal component variable grouping detects intersample variable correlation and groups variables with similar profiles which simplifies interpretation and highlights related ions and fragments. It can also extract product ion spectra from the data collected by fragmenting a wide precursor ion window. Results:Follicular fluid from the two groups differed with respect to five metabolites. Follicular fluid from the progesterone group contained elevated levels of 8-hydroxyguanosine and 4-hydroxynonenal and reduced levels of ATP, estradiol, and L-carnitine. The increased progesterone level on the day of HCG injection could negatively impact oocyte quality, thus reducing the pregnancy rate of IVF patients. 10.1155/2018/1780391
    Multivariate data validation for investigating primary HCMV infection in pregnancy. Barberini Luigi,Noto Antonio,Saba Luca,Palmas Francesco,Fanos Vassilios,Dessì Angelica,Zavattoni Maurizio,Fattuoni Claudia,Mussap Michele Data in brief We reported data concerning the Gas Chromatography-Mass Spectrometry (GC-MS) based metabolomic analysis of amniotic fluid (AF) samples obtained from pregnant women infected with Human Cytomegalovirus (HCMV). These data support the publication "Primary HCMV Infection in Pregnancy from Classic Data towards Metabolomics: an Exploratory analysis" (C. Fattuoni, F. Palmas, A. Noto, L. Barberini, M. Mussap, et al., 2016) [2]. GC-MS and Multivariate analysis allow to recognize the molecular phenotype of HCMV infected fetuses (transmitters) and that of HCMV non-infected fetuses (non-transmitters); moreover, GC-MS and multivariate analysis allow to distinguish and to compare the molecular phenotype of these two groups with a control group consisting of AF samples obtained in HCMV non-infected pregnant women. The obtained data discriminate controls from transmitters as well as from non-transmitters; no statistically significant difference was found between transmitters and non-transmitters. 10.1016/j.dib.2016.08.050
    Early Phthalates Exposure in Pregnant Women Is Associated with Alteration of Thyroid Hormones. Huang Po-Chin,Tsai Chih-Hsin,Liang Wei-Yen,Li Sih-Syuan,Huang Han-Bin,Kuo Pao-Lin PloS one INTRODUCTION:Previous studies revealed that phthalate exposure could alter thyroid hormones during the last trimester of pregnancy. However, thyroid hormones are crucial for fetal development during the first trimester. We aimed to clarify the effect of phthalate exposure on thyroid hormones during early pregnancy. METHOD:We recruited 97 pregnant women who were offered an amniocentesis during the early trimester from an obstetrics clinic in southern Taiwan from 2013 to 2014. After signing an informed consent form, we collected amniotic fluid and urine samples from pregnant women to analyze 11 metabolites, including mono-ethyl phthalate (MEP), mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP), mono-(2-ethylhexyl) phthalate (MEHP), mono-butyl phthalate (MnBP), of 9 phthalates using liquid chromatography/ tandem mass spectrometry. We collected blood samples from each subject to analyze serum thyroid hormones including thyroxine (T4), free T4, and thyroid-binding globulin (TBG). RESULTS:Three phthalate metabolites were discovered to be >80% in the urine samples of the pregnant women: MEP (88%), MnBP (81%) and MECPP (86%). Median MnBP and MECPP levels in pregnant Taiwanese women were 21.5 and 17.6 μg/g-creatinine, respectively, that decreased after the 2011 Taiwan DEHP scandal. Results of principal component analysis suggested two major sources (DEHP and other phthalates) of phthalates exposure in pregnant women. After adjusting for age, gestational age, TBG, urinary creatinine, and other phthalate metabolites, we found a significantly negative association between urinary MnBP levels and serum T4 (β = -5.41; p-value = 0.012; n = 97) in pregnant women using Bonferroni correction. CONCLUSION:We observed a potential change in the thyroid hormones of pregnant women during early pregnancy after DnBP exposure. Additional study is necessitated to clarify these associations. 10.1371/journal.pone.0159398
    LC-MS-based metabolomics identification of novel biomarkers of chorioamnionitis and its associated perinatal neurological damage. Dudzik Danuta,Revello Rocio,Barbas Coral,Bartha Jose L Journal of proteome research Chorioamnionitis is a complication of pregnancy associated with significant maternal and perinatal long-term adverse outcomes. We apply high-throughput amniotic fluid (AF) metabolomics analysis for better understanding the pathophysiological mechanism of chorioamnionitis and its associated perinatal neurological injury and to provide meaningful information about new potential biomarkers. AF samples (n = 40) were collected from women at risk of chorioamnionits. Detailed clinical information on each pregnancy was obtained from obstetrical and neonatal medical examination. Liquid chromatography (LC)/mass spectrometry (MS) followed by data alignment and filtration as well as univariate and multivariate statistical analysis was performed. Statistically significant differences were found in 60 masses in positive and 115 in negative ionization mode obtained with LC/quadrupole time-of-flight MS (LC-QTOF-MS) between women with and without chorioamnionitis. Identified compounds were mainly related to glycerophospholipids and sphingolipids metabolism. From them, LPE(16:0)/LPE(P-16:0) and especially lactosylceramides emerged as the best biomarker candidates. Sulfocholic acid, trioxocholenoic acids, and LPC(18:2) were particularly increased in women with chorioamnionitis whose newborns developed perinatal brain damage. Therefore, we propose LPE(16:0)/LPE(P-16:0) and lactosylceramides as biomarkers for chorioamnionitis as well as LPC(18:2), trioxocholenoic acid, and sulfocholic acid for its associated perinatal brain damage. Metabolomics fingerprinting of AF enables the prediction of pregnancy-related disorders and the development of new diagnostics strategies. 10.1021/pr501087x
    High-Resolution (1)H NMR Spectroscopy Discriminates Amniotic Fluid of Fetuses with Congenital Diaphragmatic Hernia from Healthy Controls. Croitor-Sava Anca,Beck Veronika,Sandaite Inga,Van Huffel Sabine,Dresselaers Tom,Claus Filip,Himmelreich Uwe,Deprest Jan Journal of proteome research Lung hypoplasia in congenital diaphragmatic hernia (CDH) is a life-threatening birth defect. Severe cases can be offered tracheal occlusion to boost prenatal lung development, although defining those to benefit remains challenging. Metabonomics of (1)H NMR spectra collected from amniotic fluid (AF) can identify general changes in diseased versus healthy fetuses. AF embodies lung secretions and hence might contain pulmonary next to general markers of disease in CDH fetuses. AF from 81 healthy and 22 CDH fetuses was collected. NMR spectroscopy was performed at 400 MHz to compare AF from fetuses with CDH against controls. Several advanced feature extraction methods based on statistical tests that explore spectral variability, similarity, and dissimilarity were applied and compared. This resulted in the identification of 30 spectral regions, which accounted for 80% variability between CDH and controls. Combination with automated classification discriminates AF from CDH versus healthy fetuses with up to 92% accuracy. Within the identified spectral regions, isoleucine, leucine, valine, pyruvate, GABA, glutamate, glutamine, citrate, creatine, creatinine, taurine, and glucose were the most concentrated metabolites. As the metabolite pattern of AF changes with fetal development, we have excluded metabolites with a high age-related variability and repeated the analysis with 12 spectral regions, which has resulted in similar classification accuracy. From this analysis, it was possible to distinguish between AF from CDH fetuses versus healthy controls independent of gestational age. 10.1021/acs.jproteome.5b00131
    Untargeted Metabolomic Analysis of Amniotic Fluid in the Prediction of Preterm Delivery and Bronchopulmonary Dysplasia. Baraldi Eugenio,Giordano Giuseppe,Stocchero Matteo,Moschino Laura,Zaramella Patrizia,Tran Maria Rosa,Carraro Silvia,Romero Roberto,Gervasi Maria Teresa PloS one OBJECTIVE:Bronchopulmonary dysplasia (BPD) is a serious complication associated with preterm birth. A growing body of evidence suggests a role for prenatal factors in its pathogenesis. Metabolomics allows simultaneous characterization of low molecular weight compounds and may provide a picture of such a complex condition. The aim of this study was to evaluate whether an unbiased metabolomic analysis of amniotic fluid (AF) can be used to investigate the risk of spontaneous preterm delivery (PTD) and BPD development in the offspring. STUDY DESIGN:We conducted an exploratory study on 32 infants born from mothers who had undergone an amniocentesis between 21 and 28 gestational weeks because of spontaneous preterm labor with intact membranes. The AF samples underwent untargeted metabolomic analysis using mass spectrometry combined with ultra-performance liquid chromatography. The data obtained were analyzed using multivariate and univariate statistical data analysis tools. RESULTS:Orthogonally Constrained Projection to Latent Structures-Discriminant Analysis (oCPLS2-DA) excluded effects on data modelling of crucial clinical variables. oCPLS2-DA was able to find unique differences in select metabolites between term (n = 11) and preterm (n = 13) deliveries (negative ionization data set: R2 = 0.47, mean AUC ROC in prediction = 0.65; positive ionization data set: R2 = 0.47, mean AUC ROC in prediction = 0.70), and between PTD followed by the development of BPD (n = 10), and PTD without BPD (n = 11) (negative data set: R2 = 0.48, mean AUC ROC in prediction = 0.73; positive data set: R2 = 0.55, mean AUC ROC in prediction = 0.71). CONCLUSIONS:This study suggests that amniotic fluid metabolic profiling may be promising for identifying spontaneous preterm birth and fetuses at risk for developing BPD. These findings support the hypothesis that some prenatal metabolic dysregulations may play a key role in the pathogenesis of PTD and the development of BPD. 10.1371/journal.pone.0164211
    Gestational Diabetes Alters the Metabolomic Profile in 2nd Trimester Amniotic Fluid in a Sex-Specific Manner. O'Neill Kathleen,Alexander Jacqueline,Azuma Rikka,Xiao Rui,Snyder Nathaniel W,Mesaros Clementina A,Blair Ian A,Pinney Sara E International journal of molecular sciences Maternal diabetes and obesity induce marked abnormalities in glucose homeostasis and insulin secretion in the fetus, and are linked to obesity, diabetes, and metabolic disease in the offspring, with specific metabolic characterization based on offspring sex. Gestational diabetes (GDM) has profound effects on the intrauterine milieu, which may reflect and/or modulate the function of the maternal⁻fetal unit. In order to characterize metabolic factors that affect offspring development, we profiled the metabolome of second trimester amniotic fluid (AF) from women who were subsequently diagnosed with gestational diabetes (GDM) using a targeted metabolomics approach, profiling 459 known biochemicals through gas chromatography/mass spectrometry (GC/MS) and liquid chromatography/mass spectrometry (LC/MS) assays. Using a nested case-control study design, we identified 69 total biochemicals altered by GDM exposure, while sex-specific analysis identified 44 and 58 metabolites in male and female offspring, respectively. The most significant changes were in glucose, amino acid, glutathione, fatty acid, sphingolipid, and bile acid metabolism with specific changes identified based on the offspring sex. Targeted isotope dilution LC/MS confirmatory assays measured significant changes in docosahexaenoic acid and arachidonic acid. We conclude that the sex-specific alterations in GDM maternal⁻fetal metabolism may begin to explain the sex-specific metabolic outcomes seen in offspring exposed to GDM in utero. 10.3390/ijms19092696
    Metabolomics of Human Amniotic Fluid and Maternal Plasma during Normal Pregnancy. Orczyk-Pawilowicz Magdalena,Jawien Ewa,Deja Stanislaw,Hirnle Lidia,Zabek Adam,Mlynarz Piotr PloS one Metabolic profiles of amniotic fluid and maternal blood are sources of valuable information about fetus development and can be potentially useful in diagnosis of pregnancy disorders. In this study, we applied 1H NMR-based metabolic profiling to track metabolic changes occurring in amniotic fluid (AF) and plasma (PL) of healthy mothers over the course of pregnancy. AF and PL samples were collected in the 2nd (T2) and 3rd (T3) trimester, prolonged pregnancy (PP) until time of delivery (TD). A multivariate data analysis of both biofluids reviled a metabolic switch-like transition between 2nd and 3rd trimester, which was followed by metabolic stabilization throughout the rest of pregnancy probably reflecting the stabilization of fetal maturation and development. The differences were further tested using univariate statistics at α = 0.001. In plasma the progression from T2 to T3 was related to increasing levels of glycerol, choline and ketone bodies (3-hydroxybutyrate and acetoacetate) while pyruvate concentration was significantly decreased. In amniotic fluid, T2 to T3 transition was associated with decreasing levels of glucose, carnitine, amino acids (valine, leucine, isoleucine, alanine, methionine, tyrosine, and phenylalanine) and increasing levels of creatinine, succinate, pyruvate, choline, N,N-dimethylglycine and urocanate. Lactate to pyruvate ratio was decreased in AF and conversely increased in PL. The results of our study, show that metabolomics profiling can be used to better understand physiological changes of the complex interdependencies of the mother, the placenta and the fetus during pregnancy. In the future, these results might be a useful reference point for analysis of complicated pregnancies. 10.1371/journal.pone.0152740
    The choice of amniotic fluid in metabolomics for the monitoring of fetus health. Palmas Francesco,Fattuoni Claudia,Noto Antonio,Barberini Luigi,Dessì Angelica,Fanos Vassilios Expert review of molecular diagnostics Amniotic fluid (AF) is a biological fluid in which metabolite transport is regulated by the placenta, the permeable skin, fetal lung egress and gastric fluid. During pregnancy, the composition of AF changes from similar to the interstitial fluid of the mother, to a more complex system, influenced by the fetus's urine. Since AF reflects the mother's and the fetus's health status at the same time, it may be an important diagnostic tool for a wider spectrum of clinical conditions. Indeed, the metabolic characterization of AF in relation to pathological occurrences may lead to the discovery of new biomarkers for a better clinical practice. For this reason, metabolomics may be the most suitable strategy for this task. In this review, research works on metabolomic AF analysis are discussed according to the morbidity of interest, being preterm birth/labor, gestational age and diabetes and fetal malformations, along with a number of other important studies. 10.1586/14737159.2016.1139456
    Early Pregnancy Thyroid Function Test Abnormalities in Biobank Sera from Women Clinically Diagnosed with Thyroid Dysfunction Before or After Pregnancy. Andersen Stine Linding,Olsen Jørn Thyroid : official journal of the American Thyroid Association BACKGROUND:Maternal thyroid disease may complicate pregnancy. A high frequency of abnormal thyroid function test results in pregnant women with known thyroid disease has been reported, but the frequency of unidentified thyroid dysfunction in women first clinically diagnosed with thyroid disease after a pregnancy is not known. METHODS:This was a population-based study of pregnant women in the Danish National Birth Cohort (DNBC) who had a blood sample drawn in early pregnancy and terminated the pregnancy with a singleton live-birth in the period between 1997 and 2003. Participants were all women in the DNBC who had a registration of thyroid disease before and/or up to five years after the pregnancy in nationwide health registers (n = 2445) and a 12% random sample of all women in the cohort (n = 7624). Thyrotropin and free thyroxine were measured with an immunoassay in sera stored in the Danish National Biobank. Method- and pregnancy week-specific references ranges were used for classification of thyroid function test abnormalities. RESULTS:The frequency of abnormal thyroid function in early pregnancy was 12.5% in the random sample and 35.7% among women clinically diagnosed with thyroid disease before or after blood sampling (55.7% among women on current treatment). One third of women clinically diagnosed with thyroid disease after blood sampling had unidentified thyroid dysfunction in the early pregnancy blood sample (most frequently [52.0%] unidentified hypothyroidism in women with a later diagnosis of hypothyroidism). CONCLUSIONS:More than 50% of Danish pregnant women on current treatment for thyroid disease had thyrotropin and/or free thyroxine outside the week-specific reference ranges, and the frequency of unidentified early pregnancy thyroid dysfunction in women clinically diagnosed after the pregnancy was also high. 10.1089/thy.2016.0542
    Phenylalanine and tyrosine measurements across gestation by tandem mass spectrometer on dried blood spot cards from normal pregnant women. McBride Kim L,Pluciniczak Jill,Rhyand Timothy,Bartholomew Dennis Genetics in medicine : official journal of the American College of Medical Genetics PURPOSE:Maternal phenylketonuria (MPKU) requires strict control of phenylalanine (Phe) and supplemental tyrosine (Tyr). Monitoring during pregnancy using dried blood spot (DBS) cards by tandem mass spectrometry (MS/MS) is now standard practice, however there are no Phe and Tyr reference ranges for DBS MS/MS method in healthy pregnant women. METHODS:DBS cards (63-1364 days in storage) from healthy women with singleton pregnancies were analyzed by MS/MS. Three hundred ninety DBS cards from 170 pregnancies (5/1-39/6 weeks' gestation), were tested. RESULTS:Both Phe and Tyr levels declined from the first trimester (Phe: 36.2 +/- 10.6; Tyr 25.7 +/- 9.7 µmol/L) to the second trimester (Phe 33.4+/-9.3; Tyr 21.7+/- 6.7 µmol/L) and remained stable in the third trimester (Phe 32.3 +/- 8.7; Tyr 21.0 +/- 6.6 µmol/L). Phe and Tyr levels declined over time since collection (Phe: 0.004 µmol/L per day; Tyr 0.002 µmol/L). Nomograms by gestational age were created using raw data and data adjusted for time from sample collection. Reference ranges by trimester are provided. CONCLUSIONS:Both Phe and Tyr decline quickly during the first trimester and remain relatively constant over the second and third trimesters. These nomograms will provide a valuable resource for care of MPKU. 10.1038/s41436-018-0407-8
    Iron Deficiency May Predict Greater Risk for Hypothyroxinemia: A Retrospective Cohort Study of Pregnant Women in China. Teng Xiaochun,Shan Zhongyan,Li Chenyan,Yu Xiaohui,Mao Jinyuan,Wang Weiwei,Xie Xiaochen,Du Jianling,Zhang Shaowei,Gao Zhengnan,Zhang Xiaomei,Li Ling,Fan Chenling,Teng Weiping Thyroid : official journal of the American Thyroid Association BACKGROUND:Pregnant women are highly vulnerable to iron deficiency (ID) due to the increased iron needs during pregnancy. ID decreases circulating thyroid hormone concentrations likely through impairment of iron-dependent thyroid peroxidase. The present study aimed to explore the association between ID and hypothyroxinemia in a retrospective cohort of pregnant women in China. METHODS:To investigate the relationship between ID and hypothyroxinemia, 723 pregnant women were retrospectively analyzed, including 675 and 309 women in the second and third trimesters, respectively. Trimester-specific hypothyroxinemia was defined as free thyroxine (fT4) levels below the 2.5th percentile of the reference range with normal serum thyrotropin (TSH) or TSH higher than the 97.5th percentile of the reference range in each trimester of pregnancy. Serum TSH, fT4, thyroid peroxidase antibodies, thyroglobulin antibodies, serum ferritin, soluble transferrin receptor, and urinary iodine concentrations were measured. Serum ferritin, soluble transferrin receptor, and total body iron were used to indicate the nutritional iron status. RESULTS:Cross-sectional multiple linear regression analysis showed that iron status was positively associated with serum fT4 levels in the first and second trimesters of pregnancy, but not in the third trimester. Logistic regression analysis showed that ID was an independent risk factor for hypothyroxinemia (odds ratio = 14.86 [confidence interval 2.31-95.81], p = 0.005 in the first trimester and odds ratio = 3.36 [confidence interval 1.01-11.21], p = 0.048 in the second trimester). The prospective analysis showed that pregnant women with ID during the first trimester of pregnancy had lower serum fT4 levels and a higher rate of hypothyroxinemia in the second or third trimester than those without ID. CONCLUSIONS:ID appears to be a risk factor to predict hypothyroxinemia in the first and second trimesters of pregnancy, but not in the third trimester. Pregnant women with ID in the first and second trimesters should be regarded as a high-risk group for maternal hypothyroxinemia. 10.1089/thy.2017.0491
    Diagnosis and management of subclinical hypothyroidism in pregnancy. Negro Roberto,Stagnaro-Green Alex BMJ (Clinical research ed.) In prospective studies, the prevalence of undiagnosed subclinical hypothyroidism in pregnant women ranges from 3% to 15%. Subclinical hypothyroidism is associated with multiple adverse outcomes in the mother and fetus, including spontaneous abortion, pre-eclampsia, gestational hypertension, gestational diabetes, preterm delivery, and decreased IQ in the offspring. Only two prospective studies have evaluated the impact of levothyroxine therapy in pregnant women with subclinical hypothyroidism, and the results were mixed. Subclinical hypothyroidism is defined as raised thyrotropin combined with a normal serum free thyroxine level. The normal range of thyrotropin varies according to geographic region and ethnic background. In the absence of local normative data, the recommended upper limit of thyrotropin in the first trimester of pregnancy is 2.5 mIU/L, and 3.0 mIU/L in the second and third trimester. The thyroid gland needs to produce 50% more thyroid hormone during pregnancy to maintain a euthyroid state. Consequently, most women on levothyroxine therapy before pregnancy require an increase in dose when pregnant to maintain euthyroidism. Ongoing prospective trials that are evaluating the impact of levothyroxine therapy on adverse outcomes in the mother and fetus in women with subclinical hypothyroidism will provide crucial data on the role of thyroid hormone replacement in pregnancy. 10.1136/bmj.g4929
    Association of Thyroid Function Test Abnormalities and Thyroid Autoimmunity With Preterm Birth: A Systematic Review and Meta-analysis. ,Korevaar T I M,Derakhshan Arash,Taylor Peter N,Meima Marcel,Chen Liangmiao,Bliddal Sofie,Carty David M,Meems Margreet,Vaidya Bijay,Shields Beverley,Ghafoor Farkhanda,Popova Polina V,Mosso Lorena,Oken Emily,Suvanto Eila,Hisada Aya,Yoshinaga Jun,Brown Suzanne J,Bassols Judit,Auvinen Juha,Bramer Wichor M,López-Bermejo Abel,Dayan Colin,Boucai Laura,Vafeiadi Marina,Grineva Elena N,Tkachuck Alexandra S,Pop Victor J M,Vrijkotte T G,Guxens M,Chatzi L,Sunyer J,Jiménez-Zabala A,Riaño I,Murcia M,Lu X,Mukhtar S,Delles C,Feldt-Rasmussen U,Nelson S M,Alexander E K,Chaker L,Männistö T,Walsh J P,Pearce E N,Steegers E A P,Peeters R P JAMA Importance:Maternal hypothyroidism and hyperthyroidism are risk factors for preterm birth. Milder thyroid function test abnormalities and thyroid autoimmunity are more prevalent, but it remains controversial if these are associated with preterm birth. Objective:To study if maternal thyroid function test abnormalities and thyroid autoimmunity are risk factors for preterm birth. Data Sources and Study Selection:Studies were identified through a search of the Ovid MEDLINE, EMBASE, Web of Science, the Cochrane Central Register of Controlled Trials, and Google Scholar databases from inception to March 18, 2018, and by publishing open invitations in relevant journals. Data sets from published and unpublished prospective cohort studies with data on thyroid function tests (thyrotropin [often referred to as thyroid-stimulating hormone or TSH] and free thyroxine [FT4] concentrations) or thyroid peroxidase (TPO) antibody measurements and gestational age at birth were screened for eligibility by 2 independent reviewers. Studies in which participants received treatment based on abnormal thyroid function tests were excluded. Data Extraction and Synthesis:The primary authors provided individual participant data that were analyzed using mixed-effects models. Main Outcomes and Measures:The primary outcome was preterm birth (<37 weeks' gestational age). Results:From 2526 published reports, 35 cohorts were invited to participate. After the addition of 5 unpublished data sets, a total of 19 cohorts were included. The study population included 47 045 pregnant women (mean age, 29 years; median gestational age at blood sampling, 12.9 weeks), of whom 1234 (3.1%) had subclinical hypothyroidism (increased thyrotropin concentration with normal FT4 concentration), 904 (2.2%) had isolated hypothyroxinemia (decreased FT4 concentration with normal thyrotropin concentration), and 3043 (7.5%) were TPO antibody positive; 2357 (5.0%) had a preterm birth. The risk of preterm birth was higher for women with subclinical hypothyroidism than euthyroid women (6.1% vs 5.0%, respectively; absolute risk difference, 1.4% [95% CI, 0%-3.2%]; odds ratio [OR], 1.29 [95% CI, 1.01-1.64]). Among women with isolated hypothyroxinemia, the risk of preterm birth was 7.1% vs 5.0% in euthyroid women (absolute risk difference, 2.3% [95% CI, 0.6%-4.5%]; OR, 1.46 [95% CI, 1.12-1.90]). In continuous analyses, each 1-SD higher maternal thyrotropin concentration was associated with a higher risk of preterm birth (absolute risk difference, 0.2% [95% CI, 0%-0.4%] per 1 SD; OR, 1.04 [95% CI, 1.00-1.09] per 1 SD). Thyroid peroxidase antibody-positive women had a higher risk of preterm birth vs TPO antibody-negative women (6.6% vs 4.9%, respectively; absolute risk difference, 1.6% [95% CI, 0.7%-2.8%]; OR, 1.33 [95% CI, 1.15-1.56]). Conclusions and Relevance:Among pregnant women without overt thyroid disease, subclinical hypothyroidism, isolated hypothyroxinemia, and TPO antibody positivity were significantly associated with higher risk of preterm birth. These results provide insights toward optimizing clinical decision-making strategies that should consider the potential harms and benefits of screening programs and levothyroxine treatment during pregnancy. 10.1001/jama.2019.10931
    Levothyroxine in Women with Thyroid Peroxidase Antibodies before Conception. Dhillon-Smith Rima K,Middleton Lee J,Sunner Kirandeep K,Cheed Versha,Baker Krys,Farrell-Carver Samantha,Bender-Atik Ruth,Agrawal Rina,Bhatia Kalsang,Edi-Osagie Edmond,Ghobara Tarek,Gupta Pratima,Jurkovic Davor,Khalaf Yacoub,MacLean Marjory,McCabe Christopher,Mulbagal Khashia,Nunes Natalie,Overton Caroline,Quenby Siobhan,Rai Raj,Raine-Fenning Nick,Robinson Lynne,Ross Jackie,Sizer Andrew,Small Rachel,Tan Alex,Underwood Martyn,Kilby Mark D,Boelaert Kristien,Daniels Jane,Thangaratinam Shakila,Chan Shiao Y,Coomarasamy Arri The New England journal of medicine BACKGROUND:Thyroid peroxidase antibodies are associated with an increased risk of miscarriage and preterm birth, even when thyroid function is normal. Small trials indicate that the use of levothyroxine could reduce the incidence of such adverse outcomes. METHODS:We conducted a double-blind, placebo-controlled trial to investigate whether levothyroxine treatment would increase live-birth rates among euthyroid women who had thyroid peroxidase antibodies and a history of miscarriage or infertility. A total of 19,585 women from 49 hospitals in the United Kingdom underwent testing for thyroid peroxidase antibodies and thyroid function. We randomly assigned 952 women to receive either 50 μg once daily of levothyroxine (476 women) or placebo (476 women) before conception through the end of pregnancy. The primary outcome was live birth after at least 34 weeks of gestation. RESULTS:The follow-up rate for the primary outcome was 98.7% (940 of 952 women). A total of 266 of 470 women in the levothyroxine group (56.6%) and 274 of 470 women in the placebo group (58.3%) became pregnant. The live-birth rate was 37.4% (176 of 470 women) in the levothyroxine group and 37.9% (178 of 470 women) in the placebo group (relative risk, 0.97; 95% confidence interval [CI], 0.83 to 1.14, P = 0.74; absolute difference, -0.4 percentage points; 95% CI, -6.6 to 5.8). There were no significant between-group differences in other pregnancy outcomes, including pregnancy loss or preterm birth, or in neonatal outcomes. Serious adverse events occurred in 5.9% of women in the levothyroxine group and 3.8% in the placebo group (P = 0.14). CONCLUSIONS:The use of levothyroxine in euthyroid women with thyroid peroxidase antibodies did not result in a higher rate of live births than placebo. (Funded by the United Kingdom National Institute for Health Research; TABLET Current Controlled Trials number, ISRCTN15948785.). 10.1056/NEJMoa1812537
    Malaria in pregnancy alters l-arginine bioavailability and placental vascular development. McDonald Chloe R,Cahill Lindsay S,Gamble Joel L,Elphinstone Robyn,Gazdzinski Lisa M,Zhong Kathleen J Y,Philson Adrienne C,Madanitsa Mwayiwawo,Kalilani-Phiri Linda,Mwapasa Victor,Ter Kuile Feiko O,Sled John G,Conroy Andrea L,Kain Kevin C Science translational medicine Reducing adverse birth outcomes due to malaria in pregnancy (MIP) is a global health priority. However, there are few safe and effective interventions. l-Arginine is an essential amino acid in pregnancy and an immediate precursor in the biosynthesis of nitric oxide (NO), but there are limited data on the impact of MIP on NO biogenesis. We hypothesized that hypoarginemia contributes to the pathophysiology of MIP and that l-arginine supplementation would improve birth outcomes. In a prospective study of pregnant Malawian women, we show that MIP was associated with lower concentrations of l-arginine and higher concentrations of endogenous inhibitors of NO biosynthesis, asymmetric and symmetric dimethylarginine, which were associated with adverse birth outcomes. In a model of experimental MIP, l-arginine supplementation in dams improved birth outcomes (decreased stillbirth and increased birth weight) compared with controls. The mechanism of action was via normalized angiogenic pathways and enhanced placental vascular development, as visualized by placental microcomputerized tomography imaging. These data define a role for dysregulation of NO biosynthetic pathways in the pathogenesis of MIP and support the evaluation of interventions to enhance l-arginine bioavailability as strategies to improve birth outcomes. 10.1126/scitranslmed.aan6007
    Effect of Levothyroxine on Miscarriage Among Women With Normal Thyroid Function and Thyroid Autoimmunity Undergoing In Vitro Fertilization and Embryo Transfer: A Randomized Clinical Trial. Wang Haining,Gao Hongwei,Chi Hongbin,Zeng Lin,Xiao Wenhua,Wang Yanrong,Li Rong,Liu Ping,Wang Chen,Tian Qing,Zhou Zehong,Yang Jin,Liu Ye,Wei Rui,Mol Ben Willem J,Hong Tianpei,Qiao Jie JAMA Importance:Presence of thyroid autoantibodies in women with normal thyroid function is associated with increased risk of miscarriage. Whether levothyroxine treatment improves pregnancy outcomes among women undergoing in vitro fertilization and embryo transfer (IVF-ET) is unknown. Objective:To determine the effect of levothyroxine on miscarriage among women undergoing IVF-ET who had normal thyroid function and tested positive for thyroid autoantibodies. Design, Setting, and Participants:An open-label, randomized clinical trial involving 600 women who tested positive for the antithyroperoxidase antibody and were being treated for infertility at Peking University Third Hospital from September 2012 to March 2017. Interventions:The intervention group (n = 300) received either a 25-μg/d or 50-μg/d dose of levothyroxine at study initiation that was titrated according to the level of thyroid-stimulating hormone during pregnancy. The women in the control group (n = 300) did not receive levothyroxine. All participants received the same IVF-ET and follow-up protocols. Main Outcomes and Measures:The primary outcome was the miscarriage rate (pregnancy loss before 28 weeks of gestation, which was calculated among women who became pregnant). The secondary outcomes were clinical intrauterine pregnancy rate (fetal cardiac activity seen at sonography observation on the 30th day after the embryo transfer), and live-birth rate (at least 1 live birth after 28 weeks of gestation). Results:Among the 600 women (mean [SD] age, 31.6 [3.8] years) randomized in this trial, 567 women (94.5%) underwent IVF-ET and 565 (94.2%) completed the study. Miscarriage rates were 10.3% (11 of 107) in the intervention group and 10.6% (12 of 113) in the control group, with the absolute rate difference (RD) of -0.34% (95% CI, -8.65% to 8.12%) over the 4.5-year study period. Clinical intrauterine pregnancy rates were 35.7% (107 of 300) in the intervention group and 37.7% (113 of 300) in the control group, with an absolute RD of -2.00% (95% CI, -9.65% to 5.69%). Live-birth rates were 31.7% (95 of 300) in the intervention group and 32.3% (97 of 300) in the control group, with an absolute RD of -0.67% (95% CI, -8.09% to 6.77%). Conclusions and Relevance:Among women in China who had intact thyroid function and tested positive for antithyroperoxidase antibodies and were undergoing IVF-ET, treatment with levothyroxine, compared with no levothyroxine treatment, did not reduce miscarriage rates or increase live-birth rates. Trial Registration:Chinese Clinical Trial Registry: ChiCTR-TRC-13004097. 10.1001/jama.2017.18249
    Vitamin D Supplementation in Pregnancy and Lactation and Infant Growth. Roth Daniel E,Morris Shaun K,Zlotkin Stanley,Gernand Alison D,Ahmed Tahmeed,Shanta Shaila S,Papp Eszter,Korsiak Jill,Shi Joy,Islam M Munirul,Jahan Ishrat,Keya Farhana K,Willan Andrew R,Weksberg Rosanna,Mohsin Minhazul,Rahman Qazi S,Shah Prakesh S,Murphy Kellie E,Stimec Jennifer,Pell Lisa G,Qamar Huma,Al Mahmud Abdullah The New England journal of medicine BACKGROUND:It is unclear whether maternal vitamin D supplementation during pregnancy and lactation improves fetal and infant growth in regions where vitamin D deficiency is common. METHODS:We conducted a randomized, double-blind, placebo-controlled trial in Bangladesh to assess the effects of weekly prenatal vitamin D supplementation (from 17 to 24 weeks of gestation until birth) and postpartum vitamin D supplementation on the primary outcome of infants' length-for-age z scores at 1 year according to World Health Organization (WHO) child growth standards. One group received neither prenatal nor postpartum vitamin D (placebo group). Three groups received prenatal supplementation only, in doses of 4200 IU (prenatal 4200 group), 16,800 IU (prenatal 16,800 group), and 28,000 IU (prenatal 28,000 group). The fifth group received prenatal supplementation as well as 26 weeks of postpartum supplementation in the amount of 28,000 IU (prenatal and postpartum 28,000 group). RESULTS:Among 1164 infants assessed at 1 year of age (89.5% of 1300 pregnancies), there were no significant differences across groups in the mean (±SD) length-for-age z scores. Scores were as follows: placebo, -0.93±1.05; prenatal 4200, -1.11±1.12; prenatal 16,800, -0.97±0.97; prenatal 28,000, -1.06±1.07; and prenatal and postpartum 28,000, -0.94±1.00 (P=0.23 for a global test of differences across groups). Other anthropometric measures, birth outcomes, and morbidity did not differ significantly across groups. Vitamin D supplementation had expected effects on maternal and infant serum 25-hydroxyvitamin D and calcium concentrations, maternal urinary calcium excretion, and maternal parathyroid hormone concentrations. There were no significant differences in the frequencies of adverse events across groups, with the exception of a higher rate of possible hypercalciuria among the women receiving the highest dose. CONCLUSIONS:In a population with widespread prenatal vitamin D deficiency and fetal and infant growth restriction, maternal vitamin D supplementation from midpregnancy until birth or until 6 months post partum did not improve fetal or infant growth. (Funded by the Bill and Melinda Gates Foundation; ClinicalTrials.gov number, NCT01924013 .). 10.1056/NEJMoa1800927
    Androgens in pregnancy: roles in parturition. Makieva Sofia,Saunders Philippa T K,Norman Jane E Human reproduction update BACKGROUND:Understanding the physiology of pregnancy enables effective management of pregnancy complications that could otherwise be life threatening for both mother and fetus. A functional uterus (i) retains the fetus in utero during pregnancy without initiating stretch-induced contractions and (ii) is able to dilate the cervix and contract the myometrium at term to deliver the fetus. The onset of labour is associated with successful cervical remodelling and contraction of myometrium, arising from concomitant activation of uterine immune and endocrine systems. A large body of evidence suggests that actions of local steroid hormones may drive changes occurring in the uterine microenvironment at term. Although there have been a number of studies considering the potential role(s) played by progesterone and estrogen at the time of parturition, the bio-availability and effects of androgens during pregnancy have received less scrutiny. The aim of this review is to highlight potential roles of androgens in the biology of pregnancy and parturition. METHODS:A review of published literature was performed to address (i) androgen concentrations, including biosynthesis and clearance, in maternal and fetal compartments throughout gestation, (ii) associations of androgen concentrations with adverse pregnancy outcomes, (iii) the role of androgens in the physiology of cervical remodelling and finally (iv) the role of androgens in the physiology of myometrial function including any impact on contractility. RESULTS:Some, but not all, androgens increase throughout gestation in maternal circulation. The effects of this increase are not fully understood; however, evidence suggests that increased androgens might regulate key processes during pregnancy and parturition. For example, androgens are believed to be critical for cervical remodelling at term, in particular cervical ripening, via regulation of cervical collagen fibril organization. Additionally, a number of studies highlight potential roles for androgens in myometrial relaxation via non-genomic, AR-independent pathways critical for the pregnancy reaching term. Understanding of the molecular events leading to myometrial relaxation is an important step towards development of novel targeted tocolytic drugs. CONCLUSIONS:The increase in androgen levels throughout gestation is likely to be important for establishment and maintenance of pregnancy and initiation of parturition. Further investigation of the underlying mechanisms of androgen action on cervical remodelling and myometrial contractility is needed. The insights gained may facilitate the development of new therapeutic approaches to manage pregnancy complications such as preterm birth. 10.1093/humupd/dmu008
    Early fetal growth in progesterone-treated IVF pregnancies. Spiliopoulos D,Economides D L Archives of gynecology and obstetrics PURPOSE:The aim of this study was to compare fetal growth in the first and second trimesters of pregnancy and final birth weights between two groups of women: (a) spontaneous conceptions with reliable menstrual dates and (b) IVF pregnancies on progesterone supplementation during the first trimester. METHODS:We included in the study 73 singleton IVF pregnancies and 138 singleton spontaneous pregnancies. Exclusion criteria were: medications or presence of medical conditions affecting fetal growth. Fetal crown-rump length (CRL) at 10 + 1 to 13 + 6 weeks of gestation, and head circumference (HC), biparietal diameter (BPD), abdominal circumference (AC) and femur length (FL) at 18-24 weeks, were measured prospectively. The birth weights of the babies born were collected and compared. Independent sample t test was applied for comparing quantitative variables with normal distribution, and Wilcoxon-Mann-Whitney test was used for comparison of quantitative variables without normal distribution. RESULTS:IVF fetuses on progesterone supplementation had larger CRL measurements when compared to their counterparts from spontaneous pregnancies (p value = 0.045). Similarly, in the second trimester, the BPD was significantly larger but HC, AC and FL, although larger, did not reach statistical significance. The birthweights of babies between the two groups showed no statistically significant difference, although some IVF babies were born prematurely. CONCLUSIONS:Enhanced fetal growth during the first trimester has been observed with progesterone supplementation in IVF pregnancies. Aspects of enhanced fetal growth were observed in the second trimester but not at birth. The effect of progesterone supplementation on fetal growth needs further investigation. 10.1007/s00404-015-3951-3
    The human fetal adrenal produces cortisol but no detectable aldosterone throughout the second trimester. Johnston Zoe C,Bellingham Michelle,Filis Panagiotis,Soffientini Ugo,Hough Denise,Bhattacharya Siladitya,Simard Marc,Hammond Geoffrey L,King Peter,O'Shaughnessy Peter J,Fowler Paul A BMC medicine BACKGROUND:Human fetal adrenal glands are highly active and, with the placenta, regulate circulating progesterone, estrogen and corticosteroids in the fetus. At birth the adrenals are essential for neonate salt retention through secretion of aldosterone, while adequate glucocorticoids are required to prevent adrenal insufficiency. The objective of this study was to carry out the first comprehensive analysis of adrenal steroid levels and steroidogenic enzyme expression in normal second trimester human fetuses. METHODS:This was an observational study of steroids, messenger RNA transcripts and proteins in adrenals from up to 109 second trimester fetuses (11 weeks to 21 weeks) at the Universities of Aberdeen and Glasgow. The study design was balanced to show effects of maternal smoking. RESULTS:Concentrations of 19 intra-adrenal steroids were quantified using liquid chromatography and mass spectrometry. Pregnenolone was the most abundant steroid while levels of 17α-hydroxyprogesterone, dehydroepiandrosterone sulphate (DHEAS) and progesterone were also high. Cortisol was present in all adrenals, but aldosterone was undetected and Δ androgens were low/undetected. CYP17A1, CYP21A2 and CYP11A1 were all highly expressed and the proteins localized to the adrenal fetal zone. There was low-level expression of HSD3B and CYP11B2, with HSD3B located mainly in the definitive zone. Maternal smoking altered fetal plasma adrenocorticotropic hormone (ACTH) (P = 0.052) and intra-adrenal progesterone, 17α-hydroxyprogesterone and 16α-hydroxyprogesterone, but not plasma or intra-adrenal cortisol, or intra-adrenal DHEAS. Fetal adrenal GATA6 and NR5A1 were increased by maternal smoking. CONCLUSIONS:The human fetal adrenal gland produces cortisol but very low levels of Δ androgens and no detectable aldosterone throughout the second trimester. The presence of cortisol in fetal adrenals suggests that adrenal regulation of circulating fetal ACTH remains a factor in development of congenital adrenal hyperplasia during the second trimester, while a relative lack of aldosterone explains the salt-wasting disorders frequently seen in extreme pre-term neonates. Finally, maternal smoking may alter fetal adrenal sensitivity to ACTH, which could have knock-on effects on post-natal health. 10.1186/s12916-018-1009-7
    Influence of race on prenatal phthalate exposure and anogenital measurements among boys and girls. Wenzel Abby G,Bloom Michael S,Butts Celeste D,Wineland Rebecca J,Brock John W,Cruze Lori,Unal Elizabeth R,Kucklick John R,Somerville Stephen E,Newman Roger B Environment international BACKGROUND:Select phthalates have antiandrogenic activity, which raises concern for adverse developmental outcomes given widespread exposure of pregnant women. Investigators have reported associations between maternal urinary phthalates and altered anogenital distance (AGD), a marker of in utero androgen activity, among offspring. However, data assessing the impact of race on these associations is sparse. OBJECTIVES:To evaluate associations between prenatal phthalate exposure and AGD in a racially diverse newborn population. METHODS:We prospectively collected second trimester urine from 187 African American and 193 white mothers, and used liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) to measure eight phthalate metabolites and calculate molar sums. We measured anopenile (APD) and anoscrotal (ASD) distances of 171 boys and anoclitoral (ACD) and anofourchette (AFD) distances of 128 girls at delivery. We collected sociodemographic and clinical data from questionnaires and delivery records. RESULTS:We identified a statistically significant inverse association for mono-2-ethylhexyl phthalate (MEHP) and APD in boys (B=-1.57mm, p=0.02), which was stronger for African Americans (B=-2.07mm, p=0.04) than for whites (B=-1.23mm, p=0.22), although the racial interaction was not statistically significant (p=0.56). We found a longer ASD for higher molar sums of dibutyl phthalate (∑DBP; B=0.99mm, p=0.04), with stronger associations for whites (B=1.30mm, p=0.04) than for African Americans (B=0.39mm, p=0.59), again without a statistically significant racial interaction (p=0.34). Among girls, we found inverse associations for tertiles of MEHP with AFD and ACD, and statistically significant race-based interactions, in which ACD was longer for whites and shorter for African Americans, following exposure to monoethyl phthalate (MEP; p=0.01) and ∑DBP (p=0.08). CONCLUSIONS:Our findings suggest race and sex play important roles in phthalate-associated reproductive developmental toxicity, with important implications for designing future investigations and health interventions. 10.1016/j.envint.2017.10.007
    Progesterone and HMOX-1 promote fetal growth by CD8+ T cell modulation. Solano María Emilia,Kowal Mirka Katharina,O'Rourke Greta Eugenia,Horst Andrea Kristina,Modest Kathrin,Plösch Torsten,Barikbin Roja,Remus Chressen Catharina,Berger Robert G,Jago Caitlin,Ho Hoang,Sass Gabriele,Parker Victoria J,Lydon John P,DeMayo Francesco J,Hecher Kurt,Karimi Khalil,Arck Petra Clara The Journal of clinical investigation Intrauterine growth restriction (IUGR) affects up to 10% of pregnancies in Western societies. IUGR is a strong predictor of reduced short-term neonatal survival and impairs long-term health in children. Placental insufficiency is often associated with IUGR; however, the molecular mechanisms involved in the pathogenesis of placental insufficiency and IUGR are largely unknown. Here, we developed a mouse model of fetal-growth restriction and placental insufficiency that is induced by a midgestational stress challenge. Compared with control animals, pregnant dams subjected to gestational stress exhibited reduced progesterone levels and placental heme oxygenase 1 (Hmox1) expression and increased methylation at distinct regions of the placental Hmox1 promoter. These stress-triggered changes were accompanied by an altered CD8+ T cell response, as evidenced by a reduction of tolerogenic CD8+CD122+ T cells and an increase of cytotoxic CD8+ T cells. Using progesterone receptor- or Hmox1-deficient mice, we identified progesterone as an upstream modulator of placental Hmox1 expression. Supplementation of progesterone or depletion of CD8+ T cells revealed that progesterone suppresses CD8+ T cell cytotoxicity, whereas the generation of CD8+CD122+ T cells is supported by Hmox1 and ameliorates fetal-growth restriction in Hmox1 deficiency. These observations in mice could promote the identification of pregnancies at risk for IUGR and the generation of clinical interventional strategies. 10.1172/JCI68140
    A Randomized Trial of Progesterone in Women with Bleeding in Early Pregnancy. Coomarasamy Arri,Devall Adam J,Cheed Versha,Harb Hoda,Middleton Lee J,Gallos Ioannis D,Williams Helen,Eapen Abey K,Roberts Tracy,Ogwulu Chriscasimir C,Goranitis Ilias,Daniels Jane P,Ahmed Amna,Bender-Atik Ruth,Bhatia Kalsang,Bottomley Cecilia,Brewin Jane,Choudhary Meenakshi,Crosfill Fiona,Deb Shilpa,Duncan W Colin,Ewer Andrew,Hinshaw Kim,Holland Tom,Izzat Feras,Johns Jemma,Kriedt Kathiuska,Lumsden Mary-Ann,Manda Padma,Norman Jane E,Nunes Natalie,Overton Caroline E,Quenby Siobhan,Rao Sandhya,Ross Jackie,Shahid Anupama,Underwood Martyn,Vaithilingam Nirmala,Watkins Linda,Wykes Catherine,Horne Andrew,Jurkovic Davor The New England journal of medicine BACKGROUND:Bleeding in early pregnancy is strongly associated with pregnancy loss. Progesterone is essential for the maintenance of pregnancy. Several small trials have suggested that progesterone therapy may improve pregnancy outcomes in women who have bleeding in early pregnancy. METHODS:We conducted a multicenter, randomized, double-blind, placebo-controlled trial to evaluate progesterone, as compared with placebo, in women with vaginal bleeding in early pregnancy. Women were randomly assigned to receive vaginal suppositories containing either 400 mg of progesterone or matching placebo twice daily, from the time at which they presented with bleeding through 16 weeks of gestation. The primary outcome was the birth of a live-born baby after at least 34 weeks of gestation. The primary analysis was performed in all participants for whom data on the primary outcome were available. A sensitivity analysis of the primary outcome that included all the participants was performed with the use of multiple imputation to account for missing data. RESULTS:A total of 4153 women, recruited at 48 hospitals in the United Kingdom, were randomly assigned to receive progesterone (2079 women) or placebo (2074 women). The percentage of women with available data for the primary outcome was 97% (4038 of 4153 women). The incidence of live births after at least 34 weeks of gestation was 75% (1513 of 2025 women) in the progesterone group and 72% (1459 of 2013 women) in the placebo group (relative rate, 1.03; 95% confidence interval [CI], 1.00 to 1.07; P = 0.08). The sensitivity analysis, in which missing primary outcome data were imputed, resulted in a similar finding (relative rate, 1.03; 95% CI, 1.00 to 1.07; P = 0.08). The incidence of adverse events did not differ significantly between the groups. CONCLUSIONS:Among women with bleeding in early pregnancy, progesterone therapy administered during the first trimester did not result in a significantly higher incidence of live births than placebo. (Funded by the United Kingdom National Institute for Health Research Health Technology Assessment program; PRISM Current Controlled Trials number, ISRCTN14163439.). 10.1056/NEJMoa1813730
    Associations of Fetal Growth Outcomes with Measures of the Combined Xenoestrogenic Activity of Maternal Serum Perfluorinated Alkyl Acids in Danish Pregnant Women. Bjerregaard-Olesen Christian,Bach Cathrine Carlsen,Long Manhai,Wielsøe Maria,Bech Bodil Hammer,Henriksen Tine Brink,Olsen Jørn,Bonefeld-Jørgensen Eva Cecilie Environmental health perspectives BACKGROUND:Higher concentrations of single perfluorinated alkyl acids (PFAAs) have been associated with lower birth weight (BW), but few studies have examined the combined effects of PFAA mixtures. PFAAs have been reported to induce estrogen receptor (ER) transactivity, and estrogens may influence human fetal growth. We hypothesize that mixtures of PFAAs may affect human fetal growth by disrupting the ER. OBJECTIVES:We aimed to study the associations between the combined xenoestrogenic activity of PFAAs in pregnant women's serum and offspring BW, length, and head circumference. METHODS:We extracted the actual mixture of PFAAs from the serum of 702 Danish pregnant women (gestational wk 11–13) enrolled in the Aarhus Birth Cohort (ABC) using solid phase extraction, high-performance liquid chromatography (HPLC), and weak anion exchange. PFAA-induced xenoestrogenic receptor transactivation (XER) was determined using the stable transfected MVLN cell line. Associations between XER and measures of fetal growth were estimated using multivariable linear regression with primary adjustment for maternal age, body mass index (BMI), educational level, smoking, and alcohol intake, and sensitivity analyses with additional adjustment for gestational age (GA) (linear and quadratic). RESULTS:On average, an interquartile range (IQR) increase in XER was associated with a [Formula: see text] [95% confidence interval (CI): [Formula: see text], [Formula: see text]] decrease in BW and a [Formula: see text] (95% CI: 0.1, 0.5) decrease in birth length. Upon additional adjustment for GA, the estimated mean differences were [Formula: see text] (95% CI: [Formula: see text], 4) and [Formula: see text] (95% CI: [Formula: see text], 0.0), respectively. CONCLUSION:Higher-serum PFAA-induced xenoestrogenic activities were associated with lower BW and length in offspring, suggesting that PFAA mixtures may affect fetal growth by disrupting ER function. https://doi.org/10.1289/EHP1884. 10.1289/EHP1884
    Genetic Associations with Gestational Duration and Spontaneous Preterm Birth. Zhang Ge,Feenstra Bjarke,Bacelis Jonas,Liu Xueping,Muglia Lisa M,Juodakis Julius,Miller Daniel E,Litterman Nadia,Jiang Pan-Pan,Russell Laura,Hinds David A,Hu Youna,Weirauch Matthew T,Chen Xiaoting,Chavan Arun R,Wagner Günter P,Pavličev Mihaela,Nnamani Mauris C,Maziarz Jamie,Karjalainen Minna K,Rämet Mika,Sengpiel Verena,Geller Frank,Boyd Heather A,Palotie Aarno,Momany Allison,Bedell Bruce,Ryckman Kelli K,Huusko Johanna M,Forney Carmy R,Kottyan Leah C,Hallman Mikko,Teramo Kari,Nohr Ellen A,Davey Smith George,Melbye Mads,Jacobsson Bo,Muglia Louis J The New England journal of medicine BACKGROUND:Despite evidence that genetic factors contribute to the duration of gestation and the risk of preterm birth, robust associations with genetic variants have not been identified. We used large data sets that included the gestational duration to determine possible genetic associations. METHODS:We performed a genomewide association study in a discovery set of samples obtained from 43,568 women of European ancestry using gestational duration as a continuous trait and term or preterm (<37 weeks) birth as a dichotomous outcome. We used samples from three Nordic data sets (involving a total of 8643 women) to test for replication of genomic loci that had significant genomewide association (P<5.0×10) or an association with suggestive significance (P<1.0×10) in the discovery set. RESULTS:In the discovery and replication data sets, four loci (EBF1, EEFSEC, AGTR2, and WNT4) were significantly associated with gestational duration. Functional analysis showed that an implicated variant in WNT4 alters the binding of the estrogen receptor. The association between variants in ADCY5 and RAP2C and gestational duration had suggestive significance in the discovery set and significant evidence of association in the replication sets; these variants also showed genomewide significance in a joint analysis. Common variants in EBF1, EEFSEC, and AGTR2 showed association with preterm birth with genomewide significance. An analysis of mother-infant dyads suggested that these variants act at the level of the maternal genome. CONCLUSIONS:In this genomewide association study, we found that variants at the EBF1, EEFSEC, AGTR2, WNT4, ADCY5, and RAP2C loci were associated with gestational duration and variants at the EBF1, EEFSEC, and AGTR2 loci with preterm birth. Previously established roles of these genes in uterine development, maternal nutrition, and vascular control support their mechanistic involvement. (Funded by the March of Dimes and others.). 10.1056/NEJMoa1612665
    From Pregnancy to Preeclampsia: A Key Role for Estrogens. Berkane Nadia,Liere Philippe,Oudinet Jean-Paul,Hertig Alexandre,Lefèvre Guillaume,Pluchino Nicola,Schumacher Michael,Chabbert-Buffet Nathalie Endocrine reviews Preeclampsia (PE) results in placental dysfunction and is one of the primary causes of maternal and fetal mortality and morbidity. During pregnancy, estrogen is produced primarily in the placenta by conversion of androgen precursors originating from maternal and fetal adrenal glands. These processes lead to increased plasma estrogen concentrations compared with levels in nonpregnant women. Aberrant production of estrogens could play a key role in PE symptoms because they are exclusively produced by the placenta and they promote angiogenesis and vasodilation. Previous assessments of estrogen synthesis during PE yielded conflicting results, possibly because of the lack of specificity of the assays. However, with the introduction of reliable analytical protocols using liquid chromatography/mass spectrometry or gas chromatography/mass spectrometry, more recent studies suggest a marked decrease in estradiol levels in PE. The aim of this review is to summarize current knowledge of estrogen synthesis, regulation in the placenta, and biological effects during pregnancy and PE. Moreover, this review highlights the links among the occurrence of PE, estrogen biosynthesis, angiogenic factors, and cardiovascular risk factors. A close link between estrogen dysregulation and PE occurrence might validate estrogen levels as a biomarker but could also reveal a potential approach for prevention or cure of PE. 10.1210/er.2016-1065