Congenital heart disease in pregnancies complicated by maternal diabetes mellitus. An international clinical collaboration, literature review, and meta-analysis.

PURPOSE: Investigation of the incidence and distribution of congenital structural cardiac malformations among the offspring of mothers with diabetes type 1 and of the influence of periconceptional glycemic control. METHODS: Multicenter retrospective clinical study, literature review, and meta-analysis. The incidence and pattern of congenital heart disease in the own study population and in the literature on the offspring of type 1 diabetic mothers were compared with the incidence and spectrum of the various cardiovascular defects in the offspring of nondiabetic mothers as registered by EUROCAT Northern Netherlands. Medical records were, in addition, reviewed for HbA(1c) during the 1st trimester. RESULTS: The distribution of congenital heart anomalies in the own diabetic study population was in accordance with the distribution encountered in the literature. This distribution differed considerably from that in the nondiabetic population. Approximately half the cardiovascular defects were conotruncal anomalies. The authors' study demonstrated a remarkable increase in the likelihood of visceral heterotaxia and variants of single ventricle among these patients. As expected, elevated HbA(1c) values during the 1st trimester were associated with offspring fetal cardiovascular defects. CONCLUSION: This study shows an increased likelihood of specific heart anomalies, namely transposition of the great arteries, persistent truncus arteriosus, visceral heterotaxia and single ventricle, among offspring of diabetic mothers. This suggests a profound teratogenic effect at a very early stage in cardiogenesis. The study emphasizes the frequency with which the offspring of diabetes-complicated pregnancies suffer from complex forms of congenital heart disease. Pregnancies with poor 1st-trimester glycemic control are more prone to the presence of fetal heart disease.

Pregnancy Outcome Following Maternal Exposure To Statins: A Multicenter Prospective Study

Introduction: Statin use for the treatment of hypercholesterolemia in women of childbearing age is increasingly common. However, published data on pregnancy outcome after exposure to statins are scarce and conflicting. This contribution addresses the safety of exposure to statins during pregnancy.Method: In a multi-center (n = 11) observational, prospective study we compared the outcomes of 249 women exposed during the 1st trimester of pregnancy to simvastatin (n = 124), atorvastatin (n = 67), pravastatin (n = 32), rosuvastatin (n = 18), fluvastatin (n = 7) or cerivastatin (n = 1) with a control group exposed to agents known to be non-teratogenic (n = 249). The data were collected by members of the European Network of Teratology Information Services (ENTIS) during individual risk counseling between 1990 and 2009. Standardized procedures for data collection were used in each center.Results: The difference in the rate of major birth defects between the statin-exposed group and the control group was not statistically significant (4.0% vs. 2.7% OR 1.5; 95% CI 0.5-4.5, P = 0.44). The crude rate of spontaneous abortions (12.8% vs. 7.1%, OR 1.9, 95% CI 1.0-3.6, P = 0.04) was higher in the exposed group. However, after adjustment to maternal age and gestational age at initial contact, the difference became statistically insignificant. The rate of elective pregnancy-termination (8.8% vs. 4.4%, P = 0.05) was higher and the rate of deliveries resulting in live births was significantly lower in the statin exposed group (77.9% vs. 88.4%, P = 0.002). Prematurity was more frequent in exposed pregnancies (16.1% vs. 8.5%; OR 2.1, 95% CI 1.1-3.8, P = 0.02). Nonetheless, gestational age at birth (median 39 weeks, IQR 37-40 vs. 39 weeks, IQR 38-40, P = 0.27) and birth weight (median 3280 g, IQR 2835-3590 vs. 3250 g, IQR 2880-3600, P = 0.95) did not differ between exposed and non-exposed pregnancies.Conclusion: This study did not detect a clear teratogenic effect of statins. Its statistical power however is not sufficient to reverse the recommendation of treatment discontinuation during pregnancy. At most, the results are reassuring in case of inadvertent exposure.

Pregnancy outcome following maternal exposure to statins: a multicenter prospective study

Introduction Statin use in women of childbearing age is increasingly common. However, published data on pregnancy outcome after exposure to statins are scarce and conflicting. This contribution addresses the safety of statin use during pregnancy.Materials and Methods In a multi-centre (n = 11), prospective study we compared the outcomes of 249 women exposed during the 1st trimester of pregnancy to simvastatin (n = 124), atorvastatin (n = 67), pravastatin (n = 32), rosuvastatin (n = 18), fl uvastatin (n = 7) or cerivastatin (n = 1) with a control group exposed to agents known to be non-teratogenic (n = 249). Data were collected by members of the European Network of Teratology Information Services during individual risk counselling.Results The difference in the rate of major birth defects between the statinexposed and the control group was statistically insignificant (4.0% versus 2.7% OR 1.5; 95% CI 0.5-4.5, p = 0.44). The crude rate of spontaneous abortions (12.8% versus 7.1%, OR 1.9, 95% CI 1.0-3.6, p = 0.04) was higher in the exposed group. However, after adjustment to maternal age and gestational age at initial contact, the difference became insignificant. The rate of elective pregnancy-termination (8.8% versus 4.4%, p = 0.05) was higher and the rate of live births was lower in the exposed group (77.9% versus 88.4%, p = 0.002). Prematurity was more frequent in exposed pregnancies (16.1% versus 8.5%; OR 2.1, 95% CI 1.1- 3.8, p = 0.02). Nonetheless, gestational age at birth (median 39 weeks, IQR 37-40 versus 39 weeks, IQR 38-40, p = 0.27) and birth weight (median 3280 g, IQR 2835-3590 versus 3250 g, IQR 2880- 3600, p = 0.95) did not differ between exposed and non-exposed pregnancies.Conclusion This study did not detect a teratogenic effect of statins. Its statistical power however is not sufficient to reverse the recommendation of treatment discontinuation during pregnancy.

Appropriate management of special situations in Crohn's disease (upper gastro-intestinal; extra-intestinal manifestations; drug safety during pregnancy and breastfeeding): results of a multidisciplinary international expert panel-EPACT II

Introduction: High-grade evidence is lacking for most therapeutic decisions in Crohn's disease. Appropriateness criteria were developed for upper gastro-intestinal, extra-intestinal manifestations and drug safety during conception, pregnancy and breastfeeding in patients with Crohn's disease, to assist the physician in clinical decision making. Methods: The European Panel on the Appropriateness of Crohn's Disease Therapy (EPACT II), a multidisciplinary international European expert panel, rated clinical scenarios based on evidence from the published literature and panelists' own clinical expertise. Median ratings (on a 9-point scale) were stratified into three categories: appropriate (7-9), uncertain (4-6 with or without disagreement) and inappropriate (1-3). Experts were also asked to rank appropriate medications by priority. Results: Proton pump inhibitors, steroids, azathioprine/6-mercaptopurine and infliximab are appropriate for upper gastro-duodenal Crohn's disease; for stenosis, endoscopic balloon dilation is the first-tine therapy, although surgery is also appropriate. Ursodeoxycholic acid is the only appropriate treatment for primary sclerosing cholangitis. Infliximab is appropriate for Pyoderma gangrenosum, ankylosing spondylitis and uveitis, steroids for Pyoderma gangrenosum and ankylosing spondylitis, adalimumab for Pyoderma gangrenosum and ankylosing spondylitis, cyclosporine-A/tacrolimus for Pyoderma gangrenosum. Mesalamine, sulfasalazine, prednisone, azathioprine/6-mercaptopurine, ciprofloxacin, and probiotics, may be administered safety during pregnancy or for patients wishing to conceive, with the exception that mate patients considering conception should avoid sulfasalazine. Metronidazol is considered safe in the 2nd and 3rd trimesters whereas infliximab is rated safe in the 1st trimester but uncertain in the 2nd and 3rd trimesters. Methotrexate is always contraindicated at conception, during pregnancy or during breastfeeding, due to its known teratogenicity. Mesalamine, prednisone, probiotics and infliximab are considered safe during breastfeeding. Conclusion: EPACT II recommendations are freely available online (www.epact.ch). The validity of these criteria should now be tested by prospective evaluation. (C) 2009 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.

Topical retinoids exposure during pregnancy.

Concerns have been raised with the topical use of retinoids since the publication of occasional cases associated with characteristic retinoid embryopathy, originally described after oral use. Epidemiological data are still scant. A collaborative study was carried out to evaluate the rate of congenital malformations following 1st trimester topical retinoid exposure. Using a standardized protocol exposed pregnancies and non exposed controls were prospectively recorded by the European Network of Teratology Information Services (ENTIS). A population of 222 pregnant women exposed to topical retinoids (median age [range]: 30 [21 - 42] years; gestational week at call: 7 [3 - 35]) were compared to 444 women not exposed (median age [range]: 32 [17 - 48] years; gestational week at call: 8 [2 - 39]). The following retinoids were identified: adapalene: 22; retinoic acid: 10; tretinoin: 135; isotretinoin:49, others: 6. The exposed and non-exposed groups did not differ in maternal alcohol and tobacco use, gestational duration, birth weight and length. There were no Abstracts: Clinical Pharmacology and Therapeutics IXth World Congress -2008 significant differences between groups in the rate of pregnancies ending in spontaneous abortion (8.7% in exposed vs. 5.9% in unexposed; P=0.18) or in infants with minor malformations (3.7% in exposed vs. 2.9% in unexposed; P=0.61) and major malformations (3.7% in exposed vs. 2.2% in unexposed; P=0.29). No child showed features of retinoid embryopathy. In conclusion, these results bring reassurance in cases of fortuitous topical retinoid exposure. However, according to the current knowledge, topical retinoids can not be recommended for use during pregnancy, as the risk/benefit ratio remains questionable.

Pharmacovigilance in pregnancy: adverse drug reactions associated with fetal disorders.

Abstract Objective: To provide the first update on drug safety profiles and adverse drug reactions (ADRs) associated with fetal disorders from the Swiss national ADR database. Methods: We conducted a retrospective study using data from 202 pharmacovigilance reports on drug-associated fetal disorders from the Swiss national ADR database from 1990 to 2009. Evaluated aspects included administrative information on the report, drug exposure, and disorders. Results: The ADR reporting frequency on the topic of fetal disorders has increased during the last 20 years, from only 1 report in 1991 to a maximum of 31 reports in 2008. Nervous system drugs were the most frequently reported drug group (40.2%) above all antidepressants and antiepileptics. The highest level of overall drug intake could be observed for the 1st trimester (85.4%), especially for the first 6 weeks of pregnancy. The most frequently reported types of fetal disorders were malformations (68.8%), especially those of the musculoskeletal and circulatory systems. A positive association was discovered between antiepileptics and malformations in general and in particular of the circulatory system and the eye, ear, face, and neck. Conclusions: The results suggest that the nervous system drug group bears an especially high risk for malformations. The most commonly identified drug exposures can help focus pharmacoepidemiologic efforts in drug-induced birth defects.

Mycoplasma hominis in mid-trimester amniotic fluid : relation to pregnangy outcome

RESUME Introduction : Les naissances prématurées compliquent 6-10 % des grossesses dans les pays industrialisés et contribuent de façon notable aux taux de mortalité périnatale et de morbidité néonatale. Il a été démontré que la colonisation bactérienne du liquide amniotique joue un rôle dans l'étiologie des accouchements prématurés spontanés et des ruptures prématurées des membranes. Le but de ce travail était d'évaluer la présence de Mycoplasma hominis dans le liquide amniotique prélevé au 2eme trimestre de grossesse chez des patientes asymptomatiques et de déterminer son association avec une issue défavorable de la grossesse. Matériels et méthodes : Les échantillons de liquide amniotique de 456 patientes ayant subi une amniocentèse trans-abdominale entre les 15eme et I7eme semaines de grossesse pour diverses indications ont été testés par PCR (Polymerase Chain Reaction) afin d'identifier Mycoplasma hominis. Les produits ainsi amplifiés étaient ensuite détectés par ELISA (Enzyme-Linked Immunosorbent Assay). Les données cliniques étaient obtenues après l'accouchement. Résultats : Mycoplasma hominis a été identifié dans 29 (6,4%) des échantillons de liquide amniotique. Le taux de menace d'accouchement prématuré chez les patientes positives pour Mycoplasma hominis (14,3%) était plus élevé que chez les patientes négatives (3,3 %) (p=0,01). De même, les naissances prématurées spontanées avec membranes intactes étaient plus fréquentes chez les patientes positives (10,7%) que chez les patientes négatives (1,9 %) (p=0,02). Le taux de menace d'accouchement prématuré lors d'une grossesse antérieure était plus de trois fois plus élevé chez les patientes positives, cependant ce résultat n'était pas statistiquement significatif. Finalement, la présence du mycoplasme n'était pas corrélée à la gestose, au retard de croissance intra-utérin ou aux anomalies chromosomiques foetales. Conclusions : Les résultats montrent que la présence de Mycoplasma hominis dans le liquide amniotique prélevé entre les 15eme et I7eme semaines d' aménorrhée chez des patientes asymptomatiques est associée à un taux plus élevé de menace d'accouchement prématuré et de naissances prématurées spontanées. La détection de ce microorganisme au 2eme trimestre de la grossesse peut donc identifier les patientes à risque de menace d'accouchement et de naissance prématurées. Abstract Objective: The relationship between detection of Mycoplasma hominis in mid-trimester amniotic fluid and subsequent pregnancy outcome was investigated. Study design: Amniotic fluids from 456 women of European background who underwent a transabdominal amniocentesis at weeks 15-17 of pregnancy were tested for M. hominis by polymerase chain reaction (PCR). The amplicons were hybridized to an internal probe and detected by ELISA. Pregnancy outcomes and clinical data were subsequently obtained. Results: M. hominis were identified in 29 (6.4%) of the amniotic fluids. The rate of preterm labor in women positive for M. hominis (14.3%) was higher than in the negative women (3.3%) (p = 0.01). Similarly, a spontaneous preterm birth with intact membranes occurred in 10.7% of the M. hominis-posltive women as opposed to only 1.9% of the negative women (p = 0.02). The presence of this mycoplasma was not correlated with fetal chromosomal aberrations, intrauterine growth restriction or preeclampsia. Conclusions: Detection of M. hominis in second-trimester amniotic fluids can identify women at increased risk for subsequent preterm labor and delivery.

Former eating disorder impairs 3rd person but not 1st person perspective taking. Does dance training help?

The mental ability to take the perspective of another person may depend on one's own bodily awareness and experience. In the present study, the former was defined as having a history of an eating disorder, and the latter variable was defined as formal experience with dance. The study used a 2 × 2 × 2 factorial design in which reaction times in two mental perspective taking tasks were compared between female dancers and non-dancers with and without a former eating disorder. Participants were asked to imagine two perspectives: i) the position of front-facing and back-facing figures (3rd person perspective taking task) and ii) that these same figures are a self reflection in a mirror (1st person perspective taking task). In both tasks, a particular hand was indicated in the presented figures, and the participants had to decide whether the hand represented their own left or right hand. Overall, responses were slower for front-facing than back-facing figures in the 3rd person perspective taking task, and for back-facing than front-facing figures in the 1st person perspective taking task. Importantly, having a former history of an eating disorder related to a decreased performance in the 3rd person perspective taking task, but only in participants without dance experience. Results from an additional control group (a history of exercise but no dance experience) indicated that dance is particularly beneficial for mental bodily perspective taking. Dance experience, more so than exercise in general, can benefit 3rd person or extrapersonal perspective taking, supporting the favourable impact this exercise has on own body processing

Myocarditis and coronary dilatation in the 1st week of life: neonatal incomplete Kawasaki disease?

Acute heart failure in the early neonatal period is rare. Normally it is due to asphyxia, severe septicaemia, a congenital heart malformation or a viral myocarditis. Kawasaki disease (KD) as a cause of an neonatal myocarditis is not an established diagnosis. KD is a vasculitis of still unknown origin occurring predominantly in infants and preschool children. KD before the age of 3 months is rare. There are only few reports about KD in the 1st month. We present a newborn who showed the cardiac symptoms of KD in the 1st week of life with coronary dilatation and myocarditis. CONCLUSION: The diagnosis of incomplete KD should be considered not only in infants but also in newborns with signs of myocarditis and coronary abnormalities. Therapy with gammaglobulins may prevent the sequelae of coronary involvement.

1st datings of ammonite-bearing Bajocian suites from Caucasus (Georgia) - K-Ar ages of volcanic hornblendes

Volcanic flows and tuffs interbedded with ammonite-bearing sediments directly correlatable with the stratotype section of the Bajocian stage have been dated for the first time within the Caucasus area. Three samples, each from a different section, allowed separation of well-preserved brown hornblende; these are considered reliable geochronometers in a region where subsequent volcanic activity occurred. The dated separates are V139: a volcanic layer probably near the base, V142 another layer near the top of the Lower Bajocian substage; V141 a boulder from a latest Bajocian volcanic conglomerate. From bottom to top, apparent ages at 173.5 +/- 2.6, 164.8 +/- 2.5 and 167.1 +/- 1.9 Ma (analytical uncertainty, 95% confidence level) respectively, can be calculated. The consistency of the results is obtained if the dated boulder is interpreted as derived from an underlying layer, The Bajocian-Bathonian boundary is much younger than commonly accepted and younger than 164 Ma.

1st radiometric dating of a paleontologically dated Bathonian level from Georgia (USSR) - Use of the cathodoluminescence for selection of suitable plagioclases

Jurassic volcanic formations interlayered with (ammonite-bearing) sediments are common in the Caucasus area; this situation is of interest for the numerical calibration of the poorly documented Jurassic portion of the time scale. However, following petrographic study on thin sections no whole-rocks can be considered reliable geochronometers due to subsequent alteration; from about 20 samples, two were selected for plagioclase dating; one (V134) is probably early Kimmeridgian in age; the other (V136) is probably located in the Lower Bathonian stage according to diagnostic ammonites. Cathodoluminescence (CTL) study has shown that sample V136 was similar to usual volcanic feldspars (blue to green colour); however, the lack of CTL of the V134 plagioclase is a character common to diagenetic feldspars; consequently, in spite of a good optical preservation, this geo-chronometer cannot give an age representative of the time of emplacement of the lava flow. We have combined CTL observation with microprobe analysis in order to document the poorly known CTL behaviour of volcanic feldspars; cations Ti4+ and Fe2+ play a major role in the CTL colour of plagioclases and are able to document the growing history of these feldspars ; phenocrysts are initially rich in Fe2+ (core of the crystals, green in colour), then richer in Ti toward the exterior; microcrysts are even richer in Ti (blue to bright blue). We have also observed that natural CTL colour was modified resulting from acid ``cleaning'' of the separated feldspars : the initial blue or green colour tends to change to yellow or violet, respectively, after acid treatment probably due to oxydation of Fe2+ toward Fe3+. X-ray and microprobe analyses both indicated that plagioclases from sample V134 was near the sodic end member (albite) suggesting a diagenetic origin in this andesitic basalt; In contrast, sample V136 contains a calcic plagioclase of common composition for a doleritic basalt. The K-Ar conventional technique was applied as a preliminary tool for radiometric analysis. The Kimmeridgian Na-plagioclase sample gave a ``rejuvenated'' (85 Ma) apparent age which confirms a late genesis for the separated plagioclase phase; this interpretation is based on CTL observation, X-ray analysis, and microprobe analysis ; these techniques are able to distinguish samples which have been submitted to diagenetic alteration from those which have not. An age consistent with the stratigraphic location has been obtained from sample V136. This age of 161 +/- 3 (2-sigma) Ma, is the first one available from a sample palaeontologically located with reasonable precision within the mid Jurassic time.

Safety of artemether-lumefantrine exposure in first trimester of pregnancy: an observational cohort.

BACKGROUND: There is limited data available regarding safety profile of artemisinins in early pregnancy. They are, therefore, not recommended by WHO as a first-line treatment for malaria in first trimester due to associated embryo-foetal toxicity in animal studies. The study assessed birth outcome among pregnant women inadvertently exposed to artemether-lumefantrine (AL) during first trimester in comparison to those of women exposed to other anti-malarial drugs or no drug at all during the same period of pregnancy. METHODS: Pregnant women with gestational age <20 weeks were recruited from Maternal Health clinics or from monthly house visits (demographic surveillance), and followed prospectively until delivery. RESULTS: 2167 pregnant women were recruited and 1783 (82.3%) completed the study until delivery. 319 (17.9%) used anti-malarials in first trimester, of whom 172 (53.9%) used (AL), 78 (24.4%) quinine, 66 (20.7%) sulphadoxine-pyrimethamine (SP) and 11 (3.4%) amodiaquine. Quinine exposure in first trimester was associated with an increased risk of miscarriage/stillbirth (OR 2.5; 1.3-5.1) and premature birth (OR 2.6; 1.3-5.3) as opposed to AL with (OR 1.4; 0.8-2.5) for miscarriage/stillbirth and (OR 0.9; 0.5-1.8) for preterm birth. Congenital anomalies were identified in 4 exposure groups namely AL only (1/164[0.6%]), quinine only (1/70[1.4%]), SP (2/66[3.0%]), and non-anti-malarial exposure group (19/1464[1.3%]). CONCLUSION: Exposure to AL in first trimester was more common than to any other anti-malarial drugs. Quinine exposure was associated with adverse pregnancy outcomes which was not the case following other anti-malarial intake. Since AL and quinine were used according to their availability rather than to disease severity, it is likely that the effect observed was related to the drug and not to the disease itself. Even with this caveat, a change of policy from quinine to AL for the treatment of uncomplicated malaria during the whole pregnancy period could be already envisaged.

Concentrations sériques de protéines placentaires au 1er trimestre dans des grossesses monofoetales et multiples après FIV : implications pour le dépistage de la trisomie 21 [First trimester serum concentrations of placental proteins in singleton and multiple IVF pregnancies: implications for Down syndrome screening]

First trimester biochemical trisomy screening is based on serum concentrations of pregnancy-associated plasma protein A (PAPP-A) and human chorionic gonadotrophin (hCG). Our aim was to confirm previously suggested modifications in serum marker concentrations after in vitro fertilisation (IVF) and embryo transfer (ET), and to assess the need of establishing normal medians for trisomy screening in these. We compared 56 singleton pregnancies obtained after ET (of which 40 in gonadotrophin stimulation cycles) with 120 gestation-matched spontaneous controls. For multiple pregnancies, 17 treated cycles were compared with 25 controls. The levels of PAPP-A, hCG, and pregnancy-specific β1-glycoprotein were determined and compared between treated and spontaneous pregnancies. Serum PAPP-A levels were reduced in pregnancies achieved after gonadotrophin-stimulated IVF and ET, and this was more pronounced in earlier gestational stages. SP1 followed the same trend, while hCG tended to be increased, and this not only in pregnancies obtained from gonadotrophin-stimulated but also from oestrogen supported cycles, and with a more pronounced effect in the later gestational ages examined here. Decreased PAPP-A together with increased hCG concentrations produce falsely elevated results in first trimester Down syndrome screening, but we do not recommend the establishment of normal medians for IVF pregnancies due to the variations in stimulation protocols.

Information and risk management during the first trimester care for pregnant women: Some reflections about the ethical challenges and the legal framework in Switzerland. [L'information et la gestion des risques dans le suivi de la grossesse lors du 1er trimestre : quelques réflexions sur le défi éthique et le cadre légal en Suisse.]

The progress in prenatal medicine raises complex questions with respect to the physician-patient relationship. The physician needs to reconcile medical aspects, ethical principles as well as judicial norms. Already, during the first trimester, the physician has to put into practice the schedule combining for each individual pregnancy physical, laboratory and other appropriate exams. Physicians are under the obligation to inform in a clear and comprehensive way without creating unnecessary anxiety for their patients. Legal requirements include informed consent, the respect for the patient's right to self-determination, and compliance with the Swiss federal law on genetic testing, especially with its articles on prenatal screening and diagnosis. This article discusses the complexity of obstetrical practice when it comes to delivering adequate information within the scope of ethical and legal requirements in Switzerland. L'évolution de la médecine prénatale soulève des enjeux complexes dans la relation médecin-patient. Il s'agit de concilier à la fois les aspects médicaux, les principes éthiques et les normes juridiques. Dès le premier trimestre de la grossesse le médecin doit poser le cadre du suivi et des examens appropriés pour chaque grossesse. Son devoir est d'informer de manière claire et précise sans inquiéter inutilement, en respectant l'exigence légale d'un consentement éclairé et plus largement le droit de la patiente à l'autodétermination ainsi que le cadre de la loi fédérale suisse sur l'analyse génétique humaine dans le domaine du dépistage et du diagnostic prénatal. Cet article discute de la complexité de l'information et de l'application des principes éthiques et légaux dans la pratique obstétricale en Suisse.