Despite the general advice of avoiding medication during pregnancy, the majority of pregnant woman use one or more ‘over the counter’ analgesics. During the last few years there has been growing evidence that analgesic exposure, such as paracetamol, ibuprofen or indomethacin, during pregnancy can have detrimental effects on rodent and human fetal gonads. The majority of previous studies have focused in alterations in testosterone production and male reproductive disorders. However, few studies have analysed the effect of these analgesics on fetal germ cells and possible consequences on fertility. During my thesis, I first focused on the effect of paracetamol and indomethacin exposure during pregnancy on rat fetal gonads. These showed that both paracetamol and indomethacin are able to alter the expression of genes important for fetal gonad and germ cell development. Previous studies on germ cells and analgesics have focused on rat models, but there is a lack of similar studies performed in human models. Therefore, I investigated the consequences of exposure of therapeutically relevant doses of paracetamol and ibuprofen on human gonads, with a special attention to the germ cells. Fetal gonads from the 1st and 2nd trimester were used in two different models: hanging drop cultures for 1st trimester testes and ovaries and a xenograft system for 2nd trimester fetal testes. Fetal gonad culture in the presence of paracetamol or ibuprofen reduced AP2γ+ (gonocyte) GC number in both 1st trimester fetal testes (22-28% reduction) and ovaries (43-49% reduction). 2nd trimester fetal testes were exposed to three different regimes, 1 or 7 days paracetamol and 7 days ibuprofen, which led to reductions of 17% and 30%, respectively in AP2γ+ GC number for paracetamol and a 53% reduction in total germ cell number for ibuprofen.

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No. of bitstreams: 2 license_rdf: 22974 bytes, checksum: 99c771d9f0b9c46790009b9874d49253 (MD5) aline_nogueira_alves_santiago.pdf: 3992386 bytes, checksum: b8ec3c32c9f964b34275b2319b6b3edf (MD5) Previous issue date: 2015 / Um anodo perme?vel a fluido constitu?do por filme fino de di?xido de estanho dopado com antim?nio (Sb-SnO2) foi preparado por decomposi??o t?rmica sobre suporte de tela de a?o ASTM 316 e utilizado em reator eletroqu?mico do tipo filtro-prensa. O filme e o p? do ?xido foram investigados pelas t?cnicas de energia dispersiva de raios-X (EDX), difratometria de raios-X (DRX) e microscopia eletr?nica de varredura (MEV). O estudo do EDX indicou uma raz?o efetiva Sb/Sn maior que a nominal devido a volatiliza??o do Sn. O DRX revelou que o SnO2 est? presente na estrutura rutila, n?o sendo verificado a presen?a de picos relacionados ao ?xido de antim?nio devido sua baixa concentra??o. O estudo de MEV revelou a forma??o de filme compacto e n?o poroso, com presen?a de cristalitos superficiais. Para a caracteriza??o eletroqu?mica do anodo Sb-SnO2 foi realizado estudo de voltametria c?clica, sendo obtido a partir da curva voltam?trica uma baixa densidade superficial de carga, ou seja, o eletrodo ? de morfologia compacta. A curva de polariza??o revelou que o sobrepotencial para a rea??o de desprendimento de oxig?nio (RDO) ? de aproximadamente 1,75 V/ECS. O anodo Sb-SnO2 alojado numa c?lula filtro-prensa na condi??o de ?zero-gap? foi utilizado na degrada??o eletroqu?mica individual dos f?rmacos Diclofenaco S?dico e Paracetamol (Acetominofeno) na total aus?ncia de eletr?litos l?quidos. Os fatores que influenciam a taxa de degrada??o, tais como a densidade de corrente aplicada (5?25 mA/cm2) e a concentra??o inicial dos f?rmacos (30?70 mg/L) foram avaliados. A degrada??o dos f?rmacos seguiu a cin?tica de pseudo-primeira ordem, sendo monitorada por an?lise da demanda qu?mica de oxig?nio (DQO), cromatografia l?quida de alta efici?ncia (CLAE) e espectros na regi?o do ultravioleta-vis?vel (Uv/Vis). Foram verificadas taxas de degrada??es superiores a 80% ap?s 3,5 h de rea??o com a gera??o de subprodutos. O grau de instabilidade do eletrodo foi avaliado em fun??o do seu tempo de uso. O anodo Sb-SnO2 apresentou uma boa efic?cia para a remo??o dos f?rmacos Diclofenaco S?dico e Paracetamol (Acetominofeno) dissolvidos em ?guas, mas com um curto tempo de vida ?til. / Disserta??o (Mestrado) ? Programa de P?s-Gradua??o em Qu?mica, Universidade Federal dos Vales do Jequitinhonha e Mucuri, 2015. / ABSTRACT A fluid-permeable thin film anode composed by tin dioxide doped with antimony (Sb-SnO2) was prepared by thermal decomposition onto a ASTM 316 stainless steel screen support, and applied in a filter-press electrochemical reactor. The film and the oxide powder were investigated by the energy dispersive x-ray (EDX), X-ray diffraction (XRD) and scanning electron microscopy (SEM) techniques. The EDX study revealed an effective Sb/Sn ratio higher than the nominal one due to the volatilization of Sn. The XRD revealed that SnO2 is present as a rutila structure, not being verified the occurrence of peaks related to the antimony oxide due its low concentration. SEM analysis showed the formation of compact and non-porous film, with the presence of surface crystallites. For the electrochemical characterization of the Sb-SnO2, it was carried out a cyclic voltammetry study, being obtained from the voltammetric curve a low surface charge density, i.e., the electrode has a compact morphology. The polarization curve showed that the overpotential for the oxygen evolution reaction (OER) is about 1.75 V/SCE. The Sb-SnO2 anode housed in a filter-press cell in the zero-gap condition was applied on the electrochemical degradation of the Sodium Diclofenac and Paracetamol (acetominophen) drugs in the total absence of liquid electrolytes. Factors affecting the degradation rate, such as the applied current density (5?25 mA/cm2) and the initial concentration of drugs (30?70 mg/L) were evaluated. The degradation of drugs followed the pseudo first-order kinetics, being monitored by analysis of the chemical oxygen demand (COD), high performance liquid chromatography (HPLC) and spectra in the ultraviolet-visible (UV/Vis) region. It was verified degradation rates higher than 80% after 3.5 h of reaction with the formation of byproducts. The degree of electrode instability was evaluated as a function of its use time. The Sb-SnO2 anode exhibited a good efficiency for the removal of the drugs Diclofenac and Paracetamol (acetominophen) dissolved in water, but with a short service life.

Ce travail a pour objectif de développer un procédé couplant séparation membranaire et oxydation (photo-) Fenton hétérogène pour l’élimination du paracétamol dans l’eau. La réaction a d’abord été étudiée avec le fer en solution à pH acide (2,6) pour servir de référence aux études hétérogènes ultérieures. La méthodologie des plans d’expériences a permis de déterminer les paramètres influents (parmi température, concentrations d’oxydant et de catalyseur) et leurs interactions, et de modéliser les performances du procédé homogène. Des oxydes de fer sous la forme de particules nano- et micro-structurées (hématite, maghémite et magnétite) ou supportés sur zéolithes (type MFI ou BEA) ont ensuite été testés comme catalyseurs de l’oxydation Fenton. Pour chaque système étudié, on a évalué la conversion du polluant et du Carbone Organique Total (COT), mais aussi la stabilité du catalyseur : quantité de fer lixivié et activité du métal passé en solution (pour découpler la contribution du mécanisme homogène associé). L’effet des paramètres opératoires a ensuite été à nouveau évalué pour les catalyseurs sélectionnés (magnétite nanostructurée et Fe/MFI). Pour l’oxyde non supporté, l’étude met en évidence le rôle positif d’une augmentation de la température. A température et pH donnés, le rapport initial [oxyde de fer] / [H2O2] apparaît aussi comme le paramètre essentiel qui contrôle le taux de minéralisation, avec une inhibition de la réaction lorsque H2O2 est en trop large excès. Au contraire, pour le catalyseur Fe/MFI, une augmentation de la concentration d’oxydant se révèle bénéfique (sa consommation étant pratiquement totale dans tous les cas), et il y a peu d’effet de la température. Par ailleurs, la magnétite se révèle efficace à pH acide uniquement, tandis que le catalyseur supporté présente la même activité avec ou sans acidification préalable. L’irradiation UV améliore les performances de ces deux catalyseurs avec un abattement du COT en solution jusqu’à 70% en 5 heures, contre 98% pour le système homogène dans des conditions similaires. Les premiers tests en continu avec des particules de Fe/MFI retenues par une membrane d’ultrafiltration immergée sont prometteurs, puisque l’activité est restée stable pendant plus de 40 h. / This work aims to develop a process coupling membrane separation and heterogeneous (photo-) Fenton oxidation for the elimination of paracetamol in water. The reaction was first studied with dissolved iron in acidic solution (pH 2.6), as a reference for the subsequent heterogeneous studies. The methodology of experimental design was used to determine the significant parameters (including temperature, oxidant and catalyst concentrations) and their interactions, and to model the performance of the homogeneous process. Iron oxides as nano- and micro-structured particles (hematite, maghemite and magnetite) or supported on zeolites (MFI or BEA type) were then tested as catalysts for the Fenton oxidation. For each studied system the conversions of pollutant and Total Organic Carbon (TOC) were evaluated, as well as the catalyst stability: amount and activity of leached iron (in order to decouple the contribution of homogeneous mechanism). The effect of process parameters was then again evaluated for the selected catalysts (nanostructured magnetite and Fe/MFI). For magnetite, the study reveals a positive effect of temperature. At given temperature and pH, the initial ratio of [iron oxide] to [H2O2] also appears as a key parameter that controls the mineralization yield, with an inhibition of the reaction when H2O2 is in large excess. Conversely, for Fe/MFI catalyst, the increase in oxidant concentration is beneficial (oxidant being almost fully consumed in all cases), and temperature has a poor effect. Furthermore, magnetite is only effective at acidic pH, while supported catalyst exhibits same activity with or without prior acidification. UV irradiation improves the performance of these catalysts with a reduction of TOC in solution up to 70% within 5 hours, against 98% for the homogeneous system under similar conditions. The results of the first continuous test, performed with Fe/MFI particles retained by a submerged ultrafiltration membrane, are promising: a stable activity has been observed for over 40 h.

Made available in DSpace on 2014-06-11T19:29:08Z (GMT). No. of bitstreams: 0 Previous issue date: 2009-01-20Bitstream added on 2014-06-13T19:17:24Z : No. of bitstreams: 1 sequinel_r_me_araiq.pdf: 433619 bytes, checksum: 0bba9674756d622c5ec1266d31416529 (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / Este trabalho propõe o desenvolvimento de novos procedimentos analíticos voltados para a determinação de paracetamol em formulações farmacêuticas. Num primeiro momento, o procedimento foi baseado na hidrólise ácida do paracetamol (PCT) à p-aminofenol (PAP), seguido pela instantânea reação deste com p-dimetilaminocinamaldeído (p-DAC), em meio micelar, para formar um produto vermelho, o qual pôde ser monitorado por espectrofotometria (λmáx = 530 nm), 10 minutos após o início da reação. A hidrólise realizada em forno de microondas foi uma estratégia adotada como alternativa ao moroso processo de hidrólise convencional realizado em banho de água fervente. Estudos preliminares realizados em nosso laboratório, demonstraram ser efetiva a utilização de meio micelar – com dodecil sulfato de sódio (SDS), a fim de tornar o método mais sensível. Em seguida, os efeitos de todos os parâmetros envolvidos no processo analítico foram investigados em detalhes por meio de metodologias de planejamento de experimentos, para determinação das melhores condições experimentais para realização das análises. Sob as condições tidas como ideais, o método apresentou faixa linear de trabalho entre 1,3 x 10-6 – 2,6 x 10-5 mol L-1 (0,2 – 3,9 μg mL-1), com excelente coeficiente de correlação linear (r = 0,9996). O limite de detecção foi de 1,7 x 10-7 (30 ng mL-1). Num segundo momento, parte do procedimento analítico foi incorporada a um sistema automatizado de análise por injeção em fluxo com detecção espectrofotométrica. O novo procedimento analítico adotado apresentou uma ampla faixa linear de trabalho, entre 5,37 x 10-6 – 1,29 x 10-4 mol L-1 (0,8 – 19,5 μg mL-1), com coeficiente de correlação linear de 0,9998. O emprego deste sistema automatizado de análise proporcionou simplicidade e uma maior rapidez na realização das análises. Ambos os procedimentos... / This work proposes the development of new analytical procedures for the determination of paracetamol in pharmaceuticals preparations. At first moment, procedure was based in the paracetamol (PCT) acid hydrolysis to p-aminofenol (PAP), followed by the instantaneous reaction of this with p-dimethylaminocinnamaldehyde (p-DAC), in micellar media in order to form a red product, which could be monitored by spectrophotometry (λmáx = 530 nm), 10 minutes after the beginning of the reaction. The hydrolysis carried out in microwave oven was a strategy adopted like alternative to the slow conventional hydrolysis carried out in boiling water bath. Preliminary studies carried out in the laboratory, showed to be efficient the utilization of micellar media – with dodecil sulphate of sodium (SDS) in order to obtain the most sensible method. Furthermore, the effects of all parameters involved in the analytic process were investigated in details by means of experiments planning methodologies for determination of the best experimental conditions to carry out the analysis. Under the ideals conditions, the method presented linear work range between 1.3 x 10-6 – 2.6 x 10-5 mol L-1 (0.2 – 3.9 mL-1), with excellent correlation coefficient (r = 0,9996). The limit of detection was 1.7 x 10-7 (30 ng mL-1) In a second moment, part of the analytical procedure was incorporated to an automated flow injection analysis with spectrophotometric detection. The adopted new analytical procedure presented a wide linear work range, between 5.37 x 10-6 – 1.29 x 10-4 mol L-1 (0.8 – 19.5 mL-1), with correlation coefficient of 0.9998. The employment of this automated system of analysis provided simplicity and a bigger quickness in the accomplishment of the analysis. Both the developed procedures were applied in the determination of paracetamol in medicines and were subsequently compared with the official method for the determination of PCT in pharmaceuticals formulations.

No description available.

A detailed, fundamental understanding of the surface properties of molecular crystals and their interaction with adsorbing molecules (e.g. excipients) is important for tailoring the stability of formulations and the bioavailability of Active Pharmaceutical Ingredient (APIs). Few fundamental experimental studies with surface sensitive probes have been carried out for organic molecular crystals. X-ray photoelectron spectroscopy (XPS) is an established surface analysis method in the fields of adsorption, catalysis and surface chemistry of inorganic crystals. It has high surface sensitivity, probing approximately the top 1-3 nm of a crystal, and allows surface elemental analysis combined with the determination of the chemical state of the elements. To explore the possibilities and limitations of XPS for the surface characterisation of molecular crystal systems, investigation has been made on a range of paracetamol systems, three different poloxamers and blends of paracetamol with poloxamer 188. It was found by investigations of a range of polycrystalline paracetamol forms that the C1s, N1s and O1s core level emissions from the amide group of paracetamol allow to quantify, for the first time, the influence of surface contamination and adsorbed species on the paracetamol XPS data. Results of quantitative XPS analyses must be critically evaluated taking the material and energy-specific escape depth of the photoelectron signals into account. Analysis of the polycrystalline powder samples, including two different polymorphs and various partially amorphous forms of paracetamol, indicated that the core-level shifts associated with varying intermolecular interactions do not perturb the local electronic structure variations in paracetamol enough to become detectable through chemical shifts in the core level photoemission spectra. Subsequently, large, high quality single crystals of the monoclinic form I (with facet diameters between ~5 and ~10 mm) were obtained from different solvents (methanol, ethanol, acetone) to examine the influence of the crystallisation medium on the surface properties. Small spot XPS analysis was performed in several areas across facets to examine the possible influence of roughness and other lateral inhomogeneities. Careful curve-fitting of all results reveals only minor variations in the XPS data as a function of facet orientation, crystallisation medium or degree of crystallinity. Moreover, results indicate that any variations seen in XPS data very likely stem from low-level surface contamination, which is very difficult to avoid, even in a clean-room laboratory environment. In fact, the results indicate that the level of surface contamination depends significantly on the crystallisation apparatus cleanliness. Even minute concentrations of surface active components in the solutions, i.e. below the detection level of techniques for routine analytical methods, are likely to cause significant surface concentrations on crystal facets emersed from the solutions. The study thus highlights the paramount importance of microscopic surface cleanliness when assessing macroscopic facet-specific phenomena such as contact angles. Finally, XPS was employed to analyse milled and physical mixtures of paracetamol with poloxamer 188 at different percent. At minimum mass percentages poloxamer 188 adsorbs on the paracetamol surfaces; in the presence of poloxamer 188 excess the conformation of adsorbed poloxamer on the paracetamol surface changes. Studies of radiation damage on the poloxamer samples were performed both for several pure polxamers as well as for milled mixtures with paracetamol. They allowed the proposal of radiation-induced degradation mechanisms.

Drug induced liver injury is a leading cause of human illness and a major cause of drug withdrawals from the market. A systems biology approach has the potential to aid toxicology research since toxicological responses are a consequence of multiple non-linear and interdependent biological responses. Here such an approach is developed.The glutathione pathway is a key hepatic defence mechanism and deactivates reactive metabolites before they have the chance to damage cellular proteins. However, glutathione availability is limited and can vary between individuals. As hepatic glutathione levels cannot be measured directly, two serum-based biomarkers, i.e. 5-oxoproline and ophthalmic acid, have been proposed in literature as a means of tracking glutathione depletion. This thesis aims to test the reliability of the correlation between biomarker concentration and decreasing glutathione concentration.In this study a spiral between experiments, model predictions and falsifications, model improvement, and experimental design is described. Using this approach a kinetic model of the hepatic glutathione pathway and biomarker metabolism was constructed and subsequently expanded by adding physiologically based pharmacokinetic (PBPK) models of paracetamol and the proposed biomarkers. These models have increased the understanding of the glutathione pathway. For example, the model predicted that Glutamyl-Cysteine Synthetase induction should be a highly effective way to increase the robustness of the liver to a paracetamol challenge.In addition, it was possible to qualify with increasing precision, the correlation between biomarkers and hepatic glutathione depletion. 5-Oxoproline and ophthalmic acid provide different information about the status of the glutathione pathway. 5-Oxoproline is correlated with paracetamol-glutathione conjugate formation, but not with extreme toxicity. Ophthalmic acid is a biomarker of a more advanced stage of toxicity, where the cell is unable to protect against glutathione depletion. However, care must be taken when inferring hepatic glutathione concentration. Both models demonstrate that the sensitivity of biomarkers to exposure of paracetamol, depends on the dynamics of exposure as well as on the concentrations of intracellular metabolites, such as methionine.I discuss how the methodology of biomarker assessment could be personalised with regards to individual patients and how systems toxicology could be further developed towards reliable tools for the pharmaceutical industry.

Paracetamol is a widely used non-prescription analgesic and antipyretic. Despite its wide usage, the mechanism of action of paracetamol is not fully known. It has been found that paracetamol interacts with the central cyclooxygenase system which is likely responsible for its antipyreticeffect whereas the analgesic effect of paracetamol mainly depends on cannabinoid receptor type 1 activation. Paracetamol is considered the first choice for treatment of pain and/or fever during pregnancy and can reach the developing brain following consumption since it crosses both blood-brain and placental barriers. However, increasing evidence from both animal and human studies show that developmental paracetamol exposure is associated with adverse behavioural outcomes later in life. Nonetheless, the mechanism behind paracetamol neurotoxicity is still unknown. The main aim of this study was to investigate whether adult mice neonatally exposed to paracetamol during a critical period of brain development known as brain growth spurt havealtered expression of biomarkers important for brain development. Mice were exposed to either paracetamol (30 + 30 mg / kg, 4-hour interval) or saline on postnatal day 10. The mice's brains were then dissected out when they were two months old. In this study, the brains were cryosectioned and examined by immunohistochemistry. This study shows that there is no significant difference in the protein levels of synaptophysin (SYP), a marker for synaptic density, in Cornu Ammonis subfield 3 (also known as CA3), Cornu Ammonis subfield 1 (also known as CA1), and dentate gyrus (DG) regions of adult hippocampus between paracetamol treated mice and controls. These findings suggest that previously observed adult behavioural changes after neonatal exposure to paracetamol may have other origins than effects on synaptic density using SYP marker. Further research on possible mechanisms behind paracetamol-induced adverse developmental effects is needed.

>Magister Scientiae - MSc / This project focuses on the development of simple, highly sensitive, accurate, and low cost electrochemical sensors based on the modification of pencil graphite electrodes by the electrochemical reduction of graphene oxide-metal salts as nanocomposites (ERGO-MC-PGE; MC = Sb or Au nanocomposite). The electrochemical sensors ERGO-Sb-PGE and ERGO-Au-PGE were used in the determination of paracetamol (PC) in pharmaceutical formulations using adsorptive stripping differential pulse voltammetry. The GO was prepared from graphite via a modified Hummers’ method and characterized by FTIR and Raman spectroscopy to confirm the presence of oxygen functional groups in the conjugated carbon-based structure whilst, changes in crystalline structure was observed after XRD analysis of graphite and GO. / 2023-10-07

Introduktion: Många fysiska förändringar sker under en graviditet och ibland behövs läkemedelsbehandling. Det som är viktigt att tänka på om en gravid kvinna ska läkemedelbehandlas är att många läkemedel passerar fritt över placentan vilket kan ge upphov till oönskade effekter för fostret. Ett läkemedel som passerar fritt över placentan men sägs vara säkert att använda under graviditet är det välkända och populära läkemedlet paracetamol som används som smärtlindrande och febernedsättande. Mer och mer forskning påstår att användning av paracetamol under graviditeten kan senare ge negativa konsekvenser för barnet som bland annat ökad risk för astma, ADHD och autism. Syfte: Syftet med den här litteraturstudien var att undersöka hur fostret påverkas vid intag av paracetamol under graviditeten och vilka konsekvenser det senare kan ge barnet. Material och metod: Till den här litteraturstudien eftersöktes vetenskapliga artiklar i databasen PubMed.gov under perioden 2023-02-07 – 2023-02-16. Abstract lästes igenom och exklusions- samt inklusionskriterier bestämdes vilket resulterade i totalt åtta vetenskapliga artiklar som presenteras i resultatdelen. Resultat: Studierna i det här arbetet undersökte sambandet mellan paracetamolanvändning under graviditeten och senare negativa konsekvenser för barnet. Detta samband visades i 7 av 8 studier där en ökad risk för bland annat astma, ADHD och autism påvisades men där mer forskning behövs innan ett orsakssamband kan fastställas helt. Diskussion och slutsats: Resultaten från studierna är till stor nytta för pågående forskning om de potentiella negativa konsekvenserna av paracetamolanvändning under graviditet. Även om inte ett orsakssamband kunde fastställas helt på grund av andra eventuella påverkande faktorer finns det en risk för konsekvenser vid paracetamolexponering. Däremot visade sig inte korttidsanvändning av paracetamol under graviditeten vara skadligt. Med den kunskapen bör man som gravid endast använda paracetamol i nödfall och så lite som möjligt för att minimera risken för eventuella konsekvenser. Fler och noggrannare studier behövs innan man kan fastställa ett orsakssamband. / Introduction and Background: Many physical changes occur during pregnancy and sometimes treatment with medication is necessary. What is important to bear in mind when using a drug as pregnant is that many drugs pass freely across the placenta, which can cause unwanted effects for the fetus. An example of a drug that passes freely across the placenta but is said to be safe to use during pregnancy is the well-known and popular drug paracetamol, or acetaminophen. It is used as a pain reliever and fever reducer. More research claims that the use of paracetamol during pregnancy can have negative consequences for the child, such as an increased risk of asthma, ADHD and autism.  Objective: Paracetamol is a drug that is common and is associated with harmlessness. The purpose of this literature study is to investigate how the fetus is affected when taking paracetamol during pregnancy and what later consequences it can have for the child. The goal is to increase knowledge about the subject in order to reduce the use of drugs during pregnancy if it is not really necessary. The question is: How dangerous is taking paracetamol during pregnancy and what later consequences can it have on the child?   Material and Methods: During the period 2023-02-07 – 2023-02-16, scientific articles were searched in the database PubMed.gov. Abstracts were read through and exclusion and inclusion criteria were determined which resulted in a total of eight scientific articles that are presented in the results section in this literature study.  Results: The studies that are included in this literature study investigated the association between paracetamol use during pregnancy and negative consequences for the child. This association was available in 7 out of 8 studies where an increased risk for asthma, ADHD and autism was confirmed, but more research is needed before an association can be fully established. Discussion and Conclusions: The results of the studies are of great benefit to ongoing research about the potential negative consequences of paracetamol use during pregnancy. Although a confirmed association could not be fully established due to other possible confounding’s, there is a risk of consequences with paracetamol exposure. However, short-term use of paracetamol during pregnancy was not found to be harmful. With that knowledge, pregnant woman should only use paracetamol in an emergency to minimize the risk of possible consequences. More detailed studies are needed before an association can be fully established.