Meeting Abstracts The 2nd International OTIS-ENTIS Conference at The Hospital for Sick Children, Toronto, Canada September 19–21, 2014 Fetal Risks of Drugs 1. Isotretinoin: The Mothersafe Experience 2010 to 2014. A Need to Revisit Education and Prescribing Practices Debra Kennedy,1,2 Majella Hill,1 Delwyn Cupitt,1 Bama Eswaran,1 Elizabeth Helner,1 Magie Stacey,1 and Tricia Taylor2 1
MotherSafe Royal Hospital for Women, Randwick, New South Wales, Australia, 2School of Women’s and Children’s Health, University of New South Wales, New South Wales, Australia.
Background: Isotretinoin is a known teratogen and is prescribed for the treatment of severe cystic acne resistant to other forms of treatment. Because acne is a condition that affects young women of childbearing age, the risk for inadvertent pregnancy exposure is high. Unfortunately despite its known reproductive risks, women of reproductive age are still taking the drug (often for relatively trivial acne) and without appropriate counseling and contraception, resulting in exposed pregnancies at high risk of anomalies and other adverse outcomes. In Australia, isotretinoin can only be prescribed by a consultant physician or Dermatologist. Prescriptions are for a 1-month supply but come with a maximum of three repeats, meaning that it is possible for a woman to take the drug or initiate treatment several months after a negative pregnancy test. Methods: During the period 1 January 2009 to 30 April 2014, MotherSafe received 103 calls regarding concerns about isotretinoin exposure. Results: There were 10 calls regarding paternal isotretinoin exposure and 23 regarding topical exposures. In addition, there were two women who had previous stillbirths associated with isotretinoin use and were calling about retinoid exposures in a subsequent pregnancy. The mean age of all callers regarding retinoids was 30.17 years (range 15 to 45). Oral isotretinoin users were significantly younger (mean age 8.6 weeks (range 4–24 weeks). The majority of callers (52%) were consumers. Of the 68 calls regarding oral isotretinoin, 49 (72%) were regarding potential pregnancy exposures (including 12 or 18% where the specific reason for the call was given as considering termination of pregnancy). Five calls (7%) were
Published online 7 June 2014 in Wiley Online Library (wileyonlinelibrary.com). Doi: 10.1002/bdra.23258
C 2014 Wiley Periodicals, Inc. V
regarding exposure during breastfeeding and one caller wanted general information (i.e., not currently pregnant or planning pregnancy but considering her future reproductive options in relation to taking isotretinoin. On a positive note 13 women (19%) called regarding a future pregnancy (pregnancy planning). Of concern were the number of young women who did not receive appropriate counseling or use adequate contraception. Conclusion: This small series suggests a need to review Australian prescribing and dispensing guidelines and provide more education to both consumers and healthcare providers about appropriate management and the risks of this recognized teratogen.
2. Exposure to Isotretinoin in Pregnancy: An Ongoing Problem Maya Berlin,1 Natalia Dinavitser,1 Einat Gorelik,2 Dorit Nahlieli Dil,2 and Mati Berkovitch1 1
Clinical Pharmacology and Toxicology Unit, Teratogen Information Service, Assaf Harofeh Medical Center, Tzrifin, Israel, 2Pharmacovigilance and Drug Information Department, Pharmaceutical Division, Ministry of Health, Israel.
Background: Oral isotretinoin, a vitamin A analog, was first approved by United States Food and Drug Administration (FDA) in 1982 for the treatment of severe forms of acne. Upon approval, the drug was classified as teratogenic with an estimated 25% to 35% increased risk of congenital malformations and up to a 40% increased risk for spontaneous abortions. The first Pregnancy Prevention Program (PPP) was introduced in 1988 by FDA and Roche. In 2006, the FDA initiated the iPLEDGE, the most restricted, risk reduction program; even though, in the United States there are approximately 150 isotretinoinexposed pregnancies each year. The objective of this study was to assess the extent of isotretinoin exposed pregnancies, to characterize the exposed population, and to identify potential risk factors. Methods: Inspection of all cases in the Teratology Information Services (TIS) Zerifin between the years 2011 and 2014. Follow-up interviews were performed to women/physicians who contacted our TIS seeking advice about teratogen-risk counseling regarding oral retinoid exposure in pregnancy (including isotretinoin and acitretin). Additionally, the Adverse Drug Reaction database of Israeli Ministry of Health (MOH) was reviewed, as well as
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World Health Organization (WHO) database for reports of isotretinoin exposures during pregnancy worldwide. Results: Eighteen cases of isotretinoin and one case of acitretin exposures during pregnancy were identified in our database. Of those exposed, 10 (52.6%) women performed elective abortion after the counseling, 1 (5.3%) woman had spontaneous abortion, 2 (10.5%) women delivered healthy live babies, and 6 (31.6%) were lost to follow-up. Of the 13 women interviewed, none used two methods of contraception and only 4 used one method. During this period, the Israeli MOH did not receive any spontaneous reports regarding isotretinoin exposed pregnancies. The VigiLyze program of WHO identified 100 reports of isotretinoin and 1 report of acitretin exposures during pregnancy at the same time frame. Conclusion: In Israel, there is no active pregnancy retinoid exposure prevention program. We believe that this small scale study reveals only the tip of the iceberg, and dramatic change of approach is required. Following these findings, joint committee was assembled including all the TISs in Israel, Pharmacovigilance Department of the MOH and the Israeli Dermatology Organization to establish a national pregnancy prevention program.
3. Epidemiological Profile and Continuing Exposure to Retinoids by Women of Childbearing Age in Brazil Bruno Florentino Goldani,1,2 Luisa Grave Gross,1,2 Daniela Silva Santos,1,2 Luiza Metzdorf,1,2 Alberto Mantovani Abeche,2 Maria Teresa Vieira Sanseverino,2,3 Lavinia SchulerFaccini,2,3 and Fernanda Sales Luiz Vianna2,4
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conduct a survey and describe the profile of the use of systemic retinoids in women of childbearing age. In those with confirmed exposure assess, evaluate whether the observed anomalies are compatible with standard malformation embryopathy by retinoids; in topical exposures, to analyze the pregnancy outcome. Methods: Queries in SIAT were analyzed for the period 2003 to 2013 related to women of childbearing age who used any medications with retinoids during the periconceptional period and pregnancy. Results: Ninety-six records related to retinoids consultations were located. In 2013, five consultations occurred; 2013, 3; 2011, 8; 2010, 6; 2009, 6; 2008, 7; 2007, 10; 2006, 14; 2005, 15; 2004, 14, and 2003, 10. Of this total, 63 (65%) were consultations of pregnant women with use of oral retinoids, 14 (15%) were of women planning to become pregnant; 7 (7%) were of children born with birth defects where the mother has used any medication containing retinoid; 5 (5%) were related to research at the SIAT, and 7 (7%) were related to their reasons. Thirtynine (40%) were systemic exposures, and 13 (13%) were topical, and a query was for both routes of exposure. With data from 62% of pregnant women, we obtained an average age of 29.9 years. The evaluation of topical exposures is ongoing. Conclusion: Despite the retinoid-based drugs being contraindicated for pregnant women, our results demonstrate that exposure is still occurring in Brazil. This result indicates the need for more effective measures for effective contraception as for a better surveillance in the dispensation of these drugs.
1
Faculdade de Medicina, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brasil, 2Sistema Nacional de Informac¸~ ao sobre Agentes Teratog^enicos (SIAT), Porto Alegre, Brasil, 3Departamento de Genetica e Programa de PosGraduac¸~ ao em Genetica e Biologia Molecular, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brasil, 4Programa de Pos-Graduac¸~ ao em Epidemiologia, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brasil.
Background: It is known that systemic retinoid use for dermatological purposes has major teratogenic effects among the drugs on the market, and isotretinoin best known of them. With respect to topical use, although negative outcomes of malformations have been reported, this association is not proven by this type of exposure. In any situation, pregnancy is contraindicated, and women of childbearing age who take these drugs should undergo periodic pregnancy tests. However, SIAT Teratogen Information Service of Porto Alegre, Brazil, called Sistema Nacional de Informacoes Teratogenicas (SIAT), has received several reports of unintended pregnancies during retinoid treatments. The objectives of this study were to
4. Pregnancy Outcome following In Utero Exposure to Metformin: A Prospective Comparative Observational Study Oma Diav-Citrin,1,2 Salit Steinmetz-Shoob,3 Svetlana Shechtman,1 and Asher Ornoy2 1
The Israeli Teratology Information Service, Ministry of Health, Jerusalem, Israel, 2The Hebrew University Hadassah Medical School, Jerusalem, Israel, 3The Division of Clinical Pharmacy, the Hebrew University of Jerusalem, Israel.
Background: Metformin is a biguanide oral hypoglycemic agent used in the treatment of type 2 diabetes mellitus and in polycystic ovary syndrome (PCOS). Insulin is the mainstay of therapy for diabetes during pregnancy. Human first trimester (T1) pregnancy experience with metformin is limited. The primary objective of the study was to evaluate the rate of major anomalies after T1-metforminexposure among women with pregestational diabetes or PCOS. Methods: Pregnancies of callers who contacted the Israeli Teratology Information Service regarding metformin
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treatment during pregnancy between 2000 and 2013 were prospectively collected and followed up. The outcome was compared with a group of pregnant women with pregestational diabetes treated with insulin, and a comparison group of pregnant women counseled for non-teratogenic exposure (NTE), in a similar time frame. Results: A total of 171 T1-metformin-exposed pregnancies (120 for diabetes and 51 for PCOS) were followed up and compared, with 92 pregnancies of T1insulin-treated diabetic women, and 530 NTE pregnancies. The rate of congenital anomalies excluding genetic, cytogenetic, and spontaneously resolved cardiovascular anomalies was 4.3% (6/137) in the metformin group (PCOS 2/45 [4.4%], diabetes 4/92 [4.3%]), compared with 2.5% (2/79) in the insulin group, and 1.7% (9/ 519) in the NTE group. The differences were not statistically significant. However, the rate of all cardiovascular anomalies in the metformin (4/137 [2.9%]) group, was similar to the rate in the insulin group (2/79 [2.5%]), and higher compared with the NTE (0/519 [0%]) group, but not after excluding those that spontaneously resolved. There were no cases of caudal regression syndrome. The rate of Caesarean section deliveries was higher in both the metformin 69/132 (52.2%) and insulin 45/78 (57.7%) groups compared with the NTE group (123/485 [25.4%]). Conclusion: Metformin T1 exposure does not seem to be associated with an increased teratogenic risk.
5. Pregnancy Outcome following Maternal Exposure to Metformin: Preliminary Results of a Collaborative ENTIS and Motherisk Study A. Panchaud,1,2 D. Baud,3 T. Vial,4 N. Bernard,4 E. Amar,5 U. Winterfeld,2 L.E. Rothuizen,2 A. Dautriche,6 F. Beau-Salinas,7 A. Pistelli,8 H. Dunstan,9 Y.C. Kaplan,10 M. Kadioglu kov na a,12 G. Eleftheriou,13 G. Klinger,14 Duman,11 E. Ma 2 1 T. Buclin, C. Csajka, S. Hernandez-Diaz,15 and G. Koren16 1
School of Pharmaceutical Sciences, University of Geneva and Lausanne, Geneva, Switzerland, 2STIS and Division of Clinical Pharmacology, University Hospital, Lausanne, Switzerland, 3 Materno-Fetal and Obstetrics Research Unit, University Hospital, 1011 Lausanne, Switzerland, 4Pharmacovigilance Center of Lyon, Hospices Civils de Lyon, France, 5Registre des Malformations en Rhone Alpes (REMERA), Faculte Laennec, Lyon, France, 6 Pharmacovigilance Center of Dijon, CHU, Dijon, France, 7Pharmacovigilance Center of Tours, CHRU, Tours, France, 8Centro di Riferimento Regionale di Tossicologia Perinatale, Azienda Ospedaliero Universitaria Careggi, Florence, Italy, 9UKTIS, Regional Drug and Therapeutics Centre, Newcastle upon Tyne, United Kingdom, 10Izmir Katip Celebi University Faculty of Medicine Department of Pharmacology Teratology Information Service, Izmir, Turkey, 11Karadeniz Technical University, Faculty of Med-
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icine, Department of Pharmacology, Trabzon, Turkey, 12CZTIS, 3rd Faculty of Medicine, Charles University, Prague, Czech Republic, 13Poison Control, Bergamo, Italy, 14BELTIS Rabin Medical Center and Sackler School of Medicine, University of Tel-Aviv, Tel-Aviv, Israel, 15Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, 16The Motherisk Program, The Hospital for Sick Children, Toronto, Canada.
Background: Although a meta-analysis of eight controlled studies does not indicate an increased risk of major birth defects after first trimester exposure to metformin, the amount of evaluable pregnancies (N 5 172) is low, and its safety remains to be more fully established. Our aim was to assess more extensively the outcome of pregnancies exposed to metformin. Methods: Multicenter (n 5 9), observational prospective cohort study comparing pregnancy outcomes after exposure to metformin with a matched control group of patients not exposed to teratogenic agents or to any antidiabetic drugs. Data were collected by members of the European Network of Teratology Information Services (ENTIS) between 1995 and 2013. Motherisk data collection is still ongoing. Results: A population of 323 pregnant women exposed to metformin (median age [range]: 35 [19 – 47] years; gestational week at call: 10 [4 – 39]) were compared to 327 controls (median age [range]: 35 [21 – 45] years; gestational week at call: 9 [3 – 37]). A large majority of the patients in the exposed group had pregestational diabetes (71%). Major birth defects (after exclusion of chromosomal syndromes) were more frequent in the metformin group than in controls (7.6% versus 2.5%, unadjusted odds ratio 3.2; 95% CI: 1.3–9.2, p 5 0.005). Aside from the role of non-insulin dependent diabetes, an extensive search for other confounding factors is under way. The crude rates of spontaneous abortion (11.2% versus 6.2%, p 5 0.02) and medical pregnancy-terminations (3.1% versus 0.9%, p 5 0.05) were higher in the metformin group. Rates of premature birth (A rs4680, and ABCB1 G>A/T rs2032582 predict average pain score reported by Cohort 1; however, none of the independent variables on their own were statistically significant. In addition, gravidity and OPRM1 A>G rs1799971 predict average dose consumed by Cohort 1. Each variable was predictive on its own. Conclusion: Both clinical and genetic factors play a role in predicting effectiveness of codeine analgesia and dosage requirements. Differences in dose intake and pain relief seen across certain genetic polymorphisms suggest the need for dose adjustments or alternative forms of therapy in managing post-partum pain.
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nant woman is scarce, especially after introduction of a drug on the market. In the Netherlands, a national register called pREGnant, will be developed to monitor medication use during pregnancy and outcomes of the pregnancies. The primary focus is to establish a register with good quality data, useful to increase knowledge on medication use during pregnancy. Besides that, aspects like maintenance, privacy issues, and sharing data with third parties are another important part of the project. Methods: pREGnant is an initiative of the Teratology Information Service of the Netherlands Pharmacovigilance Centre Lareb in collaboration with the Pregnancy and Infant Development (PRIDE) Study. Pregnant women are enrolled around their first prenatal care visit through their midwife or gynecologist. The pregnant women are asked to fill out Web-based questionnaires at different moments in time ( 16 weeks, at 17, and 34 weeks gestational age and 2 and 6 months after delivery). Data will be collected on maternal health, medication use, the course and outcome of pregnancy, and the health of the child. Opportunities to link information available from existing registries, like the ‘The Netherlands Perinatal Registry’ (NPR), to the self-reported data will be explored. Different facets of the registry will be validated and evaluated. Inclusion methods, participation rate, as well as sources to obtain adequate data will be determined. The quality of data collected for drug exposure will be studied by comparing data in the Web-based questionnaires versus 2-months diaries versus pharmacy records. At last, data collection for outcomes will be validated by examining data obtained through pregnant women or Health Care Professionals or data from the NPR. Results: In April 2014, eight midwifery practices and two hospitals started electronic enrollment of the pregnant women. Four midwifery practices only hand out the leaflet about the registry, which describes how the woman herself can initiate participation through the pREGnant Web site. Conclusion: A national register will be developed and validated. The most optimal set-up to collect valid data in a labor and cost extensive way will be determined.
PHARMACOVIGILLANCE 60. Growth Percentile Webtool 59. Development of a National Register for Medication Use During Pregnancy in the Netherlands Bernke te Winkel,1 Saskia Vorstenbosch,1 and Eugene van Puijenbroek1,2
Haruna Sawada Feldman,1 Jennifer Zellner,1 Smriti Rao,1 David Kopald,1 Kenneth Lyons Jones,1 and Christina Chambers1–3 1
Netherlands Pharmacovigilance Centre Lareb, ‘s-Hertogenbosch, the Netherlands, 2University of Groningen, Department of Pharmacy, Pharmacotherapy and Pharmaceutical Care, Groningen, the Netherlands.
Department of Pediatrics, University of California San Diego, California, 2Department of Family and Preventive Medicine, University of California San Diego, San Diego, California, 3Clinical Translational Research Institute, University of California San Diego, San Diego, California.
Background: Information about medication use during pregnancy and the potential risk for the fetus and preg-
Background: A physical examination for fetal alcohol spectrum disorders (FASD) yields growth measurements
1
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that currently require the examiner to use graphs to plot the measurements to determine growth percentiles. The purpose of this project was to create a Webtool to calculate growth percentiles for measurements collected for a FASD prevalence study of 5- to 7-year-old children in the city of San Diego. Methods and Results: Several anthropometric measures were collected, including weight, height, head circumference, palpebral fissure lengths, inner canthal distance, and philtrum length. With the exception of philtrum length, growth curves were based on published references. An on-line Webtool was developed by creating formulas modeled after the CDC formulas for growth calculations on NutriStat (on EpiInfo). To reduce the error in reading the curves, three staff plotted the measurements for each line on the curve for each increment of age. To ensure the readings were consistent, percentiles were re-measured for any readings that differed by more than 0.5%. The average of the three values was then calculated. Using those plotted measurements, the standard deviation was calculated using the formula based on NutriStat, and subsequently the Z score was calculated. The Z table was used to identify percentiles. Webtool percentiles were validated against percentiles yielded from plotted graphs. As clinical concerns about growth are concentrated in those that are at or below the 10th centile or at or above the 90th centile, a lower margin of error was established for measurements in the lower and upper ranges. Conclusion: The Webtool has been a useful tool for calculating growth percentiles that are traditionally determined subjectively. More validation studies will be conducted as more data points are collected to verify the accuracy of the formulas. Additionally, the age range of the Webtool will be expanded. The Webtool is currently publicly available via: http://readysetgosandiego.org/resources/providers/. 61. Concordance of Information Reported by Health Care Professionals and Study Participants to a Teratogen Surveillance Study J.L. Richardson,1,2 A. Greenall,1 S. Stephens,1,2 L.M. Yates,1,3 and S.H.L. Thomas1,2 1
UK Teratology Information Service (UKTIS), Newcastle upon Tyne Hospitals NHS Foundation Trust, United Kingdom, 2Wolfson Unit of Clinical Pharmacology, Institute of Cellular Medicine, Newcastle University, United Kingdom, 3Northern Genetics Service, International Centre for Life, Newcastle upon Tyne Hospitals NHS Foundation Trust, United Kingdom.
Background: Teratogen surveillance studies are increasingly utilizing data from electronic patient medical records compiled of information provided by health care professio-
MEETING ABSTRACTS
nals (HCPs). However, the completeness and accuracy of the clinical details within these datasets is not fully understood. In 2009/10, UKTIS performed a prospective observational study of H1N1 exposure and management in pregnancy. In this study, questionnaires requesting the same demographic/clinical details for each participant were collected from both HCPs (mainly general practitioners) and study participants (SPs). This analysis aims to test the concordance of the information reported. Methods: To test the completeness of data provision, we compared the HCP and SP response rates to each element of the questionnaire using McNemar’s chi squared analysis of paired data. Where demographic/clinical details had been provided by both responders, we tested the level of agreement in the data provided using Cohen’s kappa statistic. Results: Information was provided by both HCPs and SPs for reported pregnancies at study enrollment (n 5 664), pregnancy outcome (n 5 371), and at 6-month infant outcome (n 5 225). The analysis showed that a significantly higher number of SPs provided information in their reports concerning residential location, occupation, ethnicity, body mass index (BMI), tobacco, alcohol or recreational drug use, gravidity, family history of congenital malformations and genetic conditions, medication use, pregnancy outcome, and infant birth weight. A significantly higher number of HCPs provided information concerning pre-existing maternal medical conditions and the gestational age at pregnancy outcome. Where demographic/ clinical details were provided by both HCPs and SPs there was a poor level of agreement regarding maternal BMI, periconceptual tobacco and alcohol use, family history of congenital malformation and genetic condition, medication exposure, pregnancy complications, neonatal problems, presence of congenital malformation, and neurodevelopmental impairment. Conclusion: Our findings indicate that some details relevant to the assessment of teratogenic risk may be unreported, or potentially inaccurately reported by HCPs. As the majority of the HCP responders to the H1N1 study were general practitioners, this analysis may raise some concerns with the use of data collected from U.K. primary care record datasets in teratogen surveillance/post-marketing pregnancy safety studies. 62. Participant Recruitment to the PROTECT Pregnancy Study; a Non-interventional, Prospective Study of Self-Reported Medication Use and Obstetric Outcomes as Provided by a Cohort of Pregnant Women J.L. Richardson,1,2 S. Stephens,1,2 S.H.L. Thomas,1,2 A. LatosBielenska,3 A. Jamry-Dziurla,3 L.T.W. de Jong-van den Berg,4 P. Zetstra-van der Woude,4 M. Laursen,5 N. Dreyer,6 V. Hliva,6 S. Mt-Isa,7 and S.C.F. Blackburn6 1
UK Teratology Information Service, Newcastle upon Tyne Hospitals NHS Foundation Trust, United Kingdom, 2Wolfson Unit of
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Clinical Pharmacology, Institute of Cellular Medicine, Newcastle University, United Kingdom, 3Department of Medical Genetics, Poznan University of Medical Sciences, Poland, 4Department of Pharmacy, University of Groningen, Netherlands, 5Department of Data Delivery and Medicinal Product Statistics, National Institute for Health Data and Disease Control, Denmark, 6Department of Real-World and Late Phase Research, Quintiles, 7Imperial Clinical Trials Unit, Imperial College London, United Kingdom.
Background: Some teratogen surveillance techniques can be costly, particularly in researcher time, and occasionally confounded by a lack of important maternal information regarding concomitant risk factors such as over-thecounter or herbal medication use. Prospective selfprovision of data by pregnant women could address some of these issues providing a sufficient number of study participants can be enrolled without the introduction of alternative limitations. The PROTECT Pregnancy Study was performed as a Web-based pilot investigation of medication use and obstetric outcomes self-reported by pregnant women. It was carried out in four countries: Denmark (DK) the Netherlands (NL), Poland (PL), the United Kingdom (U.K.). A primary aim was to assess the feasibility of data collection from self-enrolled participants. We therefore used direct-to-participant advertisement methods which did not require health care professional input. Here, we compare the costs of advertisement methods used, and the demographic/clinical characteristics, and participation practices of the study sub-populations they enrolled. Methods: Advertisement methods included the postal mailing/placement of leaflets in clinical areas, online social media group campaigns, adverts in magazines, on television and websites, and via e-mails sent from online parenting/pregnancy clubs. In this analysis means were compared though one-way analysis of variance, incidences with Pearson’s chi-squared. Results: A total of 2,521 participants self-enrolled in the study. The total cost of advertisement was e40,958. Significant international differences in mean cost/participant were observed (DK e12.66, NL e23.57, PL e20.53, UK e13.07, p < 0.001). Of the total recruited participants 2065 provided information relating to the advertisement methods which notified them of the study. Significant differences in participant demographic/clinical characteristics and participation practices were observed between those recruited through the various advertisement methods. These included differences in the incidence of maternal age 35 years, body mass index 25, first trimester study enrollment, prima-gravidity, university education, alcohol use, and gestational follow-up/pregnancy outcome data provision. Conclusion: These findings suggest that direct-toparticipant advertisement of a self-completed Web-based teratogen surveillance study may require a substantial financial resource, and costs may vary by location. Use of different direct-to-participant advertisement methods may also impact
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upon the demographic/clinical characteristics and participation practices of a study population. This research received support from the IMI-JU through the PROTECT project. 63. Use of Antiepileptic Drugs in Women of Childbearing Age and during Pregnancy: Critical Appraisal of Information Provided by the Summary of Product Characteristics Ursula Winterfeld,1 Verena Gotta,1 Laura E. Rothuizen,1 Alice Panchaud,1,2 Andrea O. Rossetti,3 and Thierry Buclin1 1
Swiss Teratogen Information Service et Division de pharmacologie clinique, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland, 2Section des sciences pharmaceutiques, Faculte des sciences, Universite de Gene`ve, Universite de Lausanne, Lausanne, Switzerland, 3Departement des Neurosciences Cliniques, Centre Hospitalier Universitaire Vaudois (CHUV) et Universite de Lausanne, Lausanne, Switzerland.
Background: Health care professionals regularly read the summary of product characteristics (SmPC) as one of different sources of information on the risks of drug use in women of childbearing age and during pregnancy. The aim of this work is to present an overview of the teratogenic potential of various antiepileptic drugs and to compare these data with the information provided by the SmPCs. Methods: We conducted a literature review on the teratogenic risks of 19 antiepileptic agents. We compared the results with the information on use in women of childbearing age and during pregnancy provided by the SmPCs of 38 commercial products available in Switzerland and Germany. Results: The teratogenic risk is discussed in all SmPCs. Quantification of the risk for birth defects and numbers of published human exposed pregnancies are mostly missing. Reproductive safety information in SmPCs show poor concordance with risk levels reported in the literature. Recommendations concerning the need to monitor plasma levels and possibly perform dose adjustments during pregnancy to prevent treatment failure are missing in five Swiss and two German SmPCs. Conclusion: The information regarding use in women of childbearing age and during pregnancy provided by the SmPCs is heterogeneous and poorly reflects the current state of knowledge. Regular updates of SmPCs are warranted in order for these documents to be of reliable use for health care professionals. 64. List of the Drugs and Herbal Medicines Consumed by Brazilian Women During Pregnancy A. Salazar-Granara,1,2 M. Galvan,1 M.T.V. Sanseverino,1 A.M. Abeche,1 and L. Schuler-Faccini1–3 1
Brazilian Teratogen Information Service (SIAT), Hospital de Clınicas de Porto Alegre, Brazil, 2Center of Traditional Medicine
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and Pharmacology of the San Martin de Porres University, Peru, 3 Genetics Department of the Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
Background: The use of drugs and herbal medicines during pregnancy should be approached with caution, due to the potential deleterious effects such as miscarriage and teratogenicity, among others. Here, we establish a list of the drugs and medicinal plants used by pregnant Brazilian women who contacted the Brazilian Teratology Information Service. Methods: We analyzed 9023 clinical records from the Brazilian Teratogen Information Service (SIAT, http://gravidez-segura.org/) in Porto Alegre, Brazil, from 1990 to 2012. Results: According to the Anatomical Therapeutic Chemical (ATC) classification system, 39 groups of drugs have been registered. The 10 most common drugs are: (1) benzodiazepine (12%); (2) antiobesity drugs (10%); (3) non-steroid anti-inflammatories (9%); (4) antipsychotics (6%); (5) diuretics (6%); (6) sex hormones (6%); (7) sympathomimetics (5%); (8) antidepressants (4%); (9) antihistamines (4%); and (10) vitamins (4%). By contrast, a total of 145 herbal medicines have been registered. The 10 most used herbals are: (1) Rhamnus purshiana (Bearberry) (17%); (2) Centella asiatica (Centela) (10%); (3) Passiflora alata (Passionfruit) (10%); (4) Cassia angustifolia (Senna) (10%); (5) Ginkgo biloba (Ginkgo) (7%); (6) Fucus vesiculosis (Seaweed) (5%); (7) Mentha pipireta (Peppermint) (5%); (8) Aesculus hippocastanum (Horse-chestnut) (5%); (9) Garcinia cambogia (Gambooge) (4%); and (10) Piper methysticum (Kava) (4%). Conclusion: Considering the U.S. Food and Drug Administration risk categories, we observed drugs classified as X (benzodiazepine, sex hormones), D (non-steroids antiinflammatory, antipsychotics, sympathomimetic, and antidepressant), and C (antiobesity, antihistamine, and diuretic). On the other hand, according to the World Health Organization’s Medicinal Plants Monography, the use during pregnancy of Rhamnus purshiana, Ginkgo biloba, and Mentha pipireta, has been contraindicated; and for the four remaining plants (Passiflora alata, Centella asiatica, Aesculus hippocastanum, and Piper methysticum) it is stated that there is no information available concerning the teratogenic or non-teratogenic effects on pregnancy. In relation to Cassia angustifolia, Fucus vesiculosis, and Garcinia cambogia, we were unable to find any information. This database of common drug and herbal products used by pregnant women is, therefore, of great importance in providing appropriate information for doctors and patients in Brazil. 65. Clinical Characteristics of Pregnancies in Brazilian Women Involving the Use and Non-use of Medicinal Herbs A. Salazar-Granara,1,2 M. Galvan,1 M.T.V. Sanseverino,1 A.M. Abeche,1 and L. Schuler-Faccini1–3 1
Brazilian Teratogen Information Service (SIAT), Hospital de Clınicas de Porto Alegre, Brasil, 2Center of Traditional Medicine
MEETING ABSTRACTS
and Pharmacology of the San Martin de Porres University, Peru, Genetics Department of the Universidade Federal do Rio Grande do Sul, Porto Alegre, Brasil.
3
Background: The aim of this study was to compare the clinical characteristics of the pregnancies in Brazilian women involving the use and non-use of herbal drugs. Methods: We analyzed 9023 clinical records from the Brazilian Teratogen Information Service (SIAT, http://gravidez-segura.org/) in Porto Alegre, Brazil, from 1990 to 2012. One hundred clinical records were randomly selected from pregnant women who used herbal drugs, and the same procedure was done for the control group. Results: The mothers involved in the study resided mainly in the South region of Brazil (63% herbal users, and 59% non-herbal group). The most common maternal education was “high school completed, with 40% and 44%, respectively; followed by “university completed,” with 36% and 20%. Women over 34 years were more frequent in the herbal consumers group (24% vs. 18%) and teenage mothers (4 births) (12% vs. 2%) (Fisher test, IC 95%, p < 0.02) were significantly higher in the herbal consumers. Previous miscarriage occurred in 29% of herbal users and 21% of non-users. Addictive maternal habits were present equally in both groups (31% and 32%, respectively). The concomitant use of two or more medications was 80% and 53% (Fisher test, IC 95%, p < 0.004). Most drug and herb exposure occurred during the first trimester (65% and 36%); followed by the second trimester (29% and 48%); and few in the third trimester (6% and 15%). Conclusion: In our sample, pregnant women consuming herbal products tend to be older and with higher education than non-herbal users. Correlated to the advanced maternal age, as expected, the number of previous pregnancies and miscarriages are as well increased in the herbal group. 66. Birth Outcomes for the Pregnancies of Brazilian Women Who Use Herbal Drugs A. Salazar-Granara,1,2 M. Galvan,1 M.T.V. Sanseverino,1 A.M. Abeche,1 and L. Schuler-Faccini1–3 1
Brazilian Teratogen Information Service (SIAT), Hospital de Clınicas de Porto Alegre, Brasil, 2Center of Traditional Medicine and Pharmacology of the San Martin de Porres University, Peru, 3 Genetics Department of the Universidade Federal do Rio Grande do Sul, Porto Alegre, Brasil.
Background: The aim of this study was to compare the clinical characteristics of the birth outcomes of pregnant Brazilian women who used herbal drugs.
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Methods: We analyzed 9023 clinical records from the Brazilian Teratogen Information Service (SIAT, http://gravidez-segura.org/) in Porto Alegre, Brazil, from 1990 to 2012. Fifty clinical records were randomly selected from pregnant women who used herbal drugs, and 50 for the non-users of herbal drugs. Results: The pregnancy results were: miscarriage, 11% versus 5%; stillbirth, 2% and 7%; live birth, 83% and 88%; in the herbal and non-herbal group, respectively. Cesarean births accounted for 67% and 62%, respectively. Male sex was 60% and 48%. The Apgar newborn scores were similar in both groups. Pre-term births (less than 38 weeks) occurred in 30% and 40%; correspondingly, in the same way, the postterm births (more than 41 weeks) were 4% and 7%; also, the low birth weight (between 1500 and 2500 g) were 14% and 12%, respectively, and, macrosomic (more than 4000 g) were 7% for both. Small for gestational age was observed in 28% and 11%, correspondingly. Congenital anomalies were present in 12% in the herbal group and 42% in the non-herbal group. For all the comparisons, it was applied the Fisher exact test and the result was non-significant. Conclusion: In the sample studied, the adverse outcomes were less frequent in the herbal exposed group compared to the non-herbal users.
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screen positive were selected to receive a comprehensive FASD evaluation. Logistic regression models were constructed to determine if the PEDS was predictive of an FASD classification. Results: There were 178 children with completed evaluations. Of these, 35 received an FASD classification. Three children were classified with fetal alcohol syndrome (FAS), 25 with partial fetal alcohol syndrome (pFAS), and 7 with a preliminary classification of alcohol-related neurodevelopmental disorder (ARND). Among the 35 who were classified as FASD, 7 screened positive on both PEDS and growth, 7 were selected as random controls, 11 screened positive on growth only, and 10 screened positive on PEDS only. Screening positive on PEDS was not predictive of an FASD classification (p 5 0.85). When comparing each of the FASD classification groups to the no FASD classification group, there were no significant differences (FAS, p 5 0.56; pFAS, p 5 0.88; and ARND, p 5 0.70). Conclusion: While the PEDS was not predictive of FASD, it did identify 29% of the children who were subsequently classified with an FASD but did not screen positive on growth. Thus, although the PEDS was not specific as a screening tool, it improved sensitivity for identifying children with an FASD. The inclusion of additional completed evaluations may shed more light on the utility of the PEDS in screening for FASD.
67. Utility of PEDS for a FASD Prevalence Study in a School-Based Population
ENVIRONMENTAL DRUGS OF ABUSE AND ALCOHOL Haruna Sawada Feldman,1 Jennifer Zellner,1 Kenneth Lyons Jones,1 and Christina Chambers1–3 1
Department of Pediatrics, University of California San Diego, San Diego, California, 2Department of Family and Preventive Medicine, University of California San Diego, San Diego, California, 3Clinical Translational Research Institute, University of California San Diego, San Diego, California.
Background: The Parents’ Evaluation of Developmental Status (PEDS) questionnaire screens for developmental and behavioral problems in children, including expressive and receptive language, fine and gross motor skills, socialemotional functioning, behavioral concerns, and school performance. The objective of this cross-sectional analysis was to determine if the PEDS used as a screening tool is effective in identifying children with fetal alcohol spectrum disorder (FASD). Methods: The city of San Diego FASD prevalence study included children in the first grade from selected schools for the 2012/2013 and 2013/2014 academic years. Two screening methods (any growth measurements 25th centile, and two or more domains positive on the PEDS) were used to determine children at risk for a potential FASD classification. Children who screened positive and a random sample of children who did not
68. Utility of PEDS for a FASD Prevalence Study in a SchoolBased Population Haruna Sawada Feldman,1 Jennifer Zellner,1 Kenneth Lyons Jones,1 and Christina Chambers1–3 1
Department of Pediatrics, University of California San Diego, San Diego, California, 2Department of Family and Preventive Medicine, University of California San Diego, San Diego, California, 3Clinical Translational Research Institute, University of California San Diego, San Diego, California.
Background: The Parents’ Evaluation of Developmental Status (PEDS) questionnaire screens for developmental and behavioral problems in children, including expressive and receptive language, fine and gross motor skills, socialemotional functioning, behavioral concerns, and school performance. The objective of this cross-sectional analysis was to determine if the PEDS used as a screening tool is effective in identifying children with Fetal Alcohol Spectrum Disorders (FASD). Methods: The city of San Diego FASD prevalence study included children in the first grade from selected schools for the 2012/2013 and 2013/2014 academic years. Two screening methods (any growth measurements 25th centile,
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MEETING ABSTRACTS
and two or more domains positive on the PEDS) were used to determine children at risk for a potential FASD classification. Children who screened positive and a random sample of children who did not screen positive were selected to receive a comprehensive FASD evaluation. Logistic regression models were constructed to determine if the PEDS was predictive of an FASD classification. Results: There were 178 children with completed evaluations. Of these, 35 received an FASD classification. Three children were classified with fetal alcohol syndrome (FAS), 25 with partial fetal alcohol syndrome (pFAS), and 7 with a preliminary classification of alcohol-related neurodevelopmental disorder (ARND). Among the 35 who were classified as FASD, 7 screened positive on both PEDS and growth, 7 were selected as random controls, 11 screened positive on growth only, and 10 screened positive on PEDS only. Screening positive on PEDS was not predictive of an FASD classification (p 5 0.85). When comparing each of the FASD classification groups to the No FASD Classification group, there were no significant differences (FAS, p 5 0.56; pFAS, p 5 0.88; and ARND, p 5 0.70). Conclusion: While the PEDS was not predictive of FASD, it did identify 29% of the children who were subsequently classified with an FASD but did not screen positive on growth. Thus, although the PEDS was not specific as a screening tool, it improved sensitivity for identifying children with an FASD. The inclusion of additional completed evaluations may shed more light on the utility of the PEDS in screening for FASD. 69. Update on Teratogenic Infections: Effects on Mental Disorders Asher Ornoy
1
nal exposure to valproic acid during pregnancy is associated with a four- to five-fold increase in ASD, equally affecting about 5% of male and female children. Maternal rubella was known for decades to be associated with an increased risk of ASD, but recently influenza and fever, as well as other maternal infections during pregnancy, have also been associated with an increased rate of ASD. In addition, an increased rate of schizophrenia among the offspring was demonstrated following maternal rubella, toxoplasmosis, and influenza infections during pregnancy, as well as (bacterial) urinary tract infections. Conclusion: It is still unknown whether these associations result from the inflammatory processes in the fetal brain, from fever, or is related to the specific effects of the infective agents. Among suggested mechanisms are elevated inflammatory cytokines and oxidative stress affecting the brain. Recent studies on infected pregnant animals have also shown an increase in behavioral changes in the adult offspring. This increase in mental disorders resulting from teratogenic exposures in pregnancy is in line with other problems, first appearing in children or young adults, but originating from intrauterine insults during embryonic/fetal development. An example is the "metabolic syndrome" characterized by overweight, hypertension, cardiovascular disease, and type 2 diabetes, commonly developing in offspring of diabetic mothers at adulthood. 70. Folic Acid Supplementation for the Prevention of Birth Defects: The Experience of the Teratology Information Service of Padova a,1 Marco Braggion,1 Elena Di Matteo Cassina,1 Marta Don 1 Gianantonio, and Maurizio Clementi1
1
1
Background: The deleterious effects of most commonly known teratogenic infectious agents, e.g., rubella, cytomegalovirus (CMV), Toxoplasma, herpes, and varicella zoster, are well established. It is also known that a dramatic decrease in the rate of these, as well as of other infections (i.e. rubella, varicella zoster), can be achieved by proper immunization. Methods: Recent phase 2 clinical trials with the CMV gB/Mf59 and the DNA TransVax vaccines have demonstrated a 50% efficacy, giving some hope for effective vaccination. In spite of the well-known damaging effects of these infections on the fetal brain, causing serious neurodevelopmental disorders, knowledge on their possible effects on mental diseases was poor. Results: Studies in animals and man have shown an association between teratogenic exposures in pregnancy and autistic spectrum disorder (ASD). For example, mater-
Background: A deficiency of folic acid in early pregnancy is associated with an increased risk of congenital malformations, especially neural tube defects. A public health campaign for the promotion of the periconceptional consumption of folic acid started few years ago in Italy. Methods: To evaluate the effectiveness of the campaign, we conducted an observational study assessing women who contacted the Teratology Information Service (TIS) of Padova during their pregnancy. After the expected delivery date, women or their physicians were contacted for a follow-up telephone interview to collect information regarding the outcome of their pregnancy and the use of folic acid in their periconceptional period. Pregnancies with the last menstrual period between 1 January 2007 and 31 December 2012 were included in the study. The sample was divided into two groups: women who started
Hebrew University Hadassah Medical School and Israeli Teratogen Information Service, Ministry of Health, Jerusalem, Israel.
Teratology Information Service, Clinical Genetics Unit, Department of Women’s and Children’s Health, University of Padova, Padova, Italy.
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the folic acid supplementation before conception, and women who assumed folic acid only after confirmation of pregnancy. Results and Discussion: A total of 2473 women contacted the TIS of Padova and were available for the follow-up interview; 174 women (7%) were counseled for antiepileptic drugs exposure. Eighty-seven percent of these answered to questions regarding the intake of folic acid during pregnancy. Most of the women took folic acid during pregnancy, with a slight increase from 2007 to 2012 (from 87.1% to 94.8%) and without significant differences between the two subgroups. The supplementation was more likely taken before conception by women treated with antiepileptic drugs (22.8% vs. 11.7%, p 5 0.001). This analysis suggests that the rate of women assuming folic acid supplementation before conception is still low, even in a highly selected and sensitized population such as the one we studied. The importance of the periconceptional folic acid supplementation does not appear to have been adequately understood also by patients affected by chronic diseases requiring treatment with antiepileptic drugs, many of which interfere with the folate metabolism and increase the risk of neural tube defects and other congenital malformations. These results may be due to the high rate of unplanned pregnancies, the poor compliance to folic acid supplementation (which is often long-term) and the lack of a preconception counseling. 71. Second Case Report of Very High Chromium and Cobalt Levels in Pregnancy due to Metal-on-Metal Hip Arthroplasty M. Oppermann,1 C. Borisch,1 C. Weber-Schoendorfer,1 and C. Schaefer1 1
Pharmakovigilanz- und Beratungszentrum f€ ur Embryonaltoxikologie, Charite Universit€ atsmedizin, Spandauer Damm, Berlin, Germany.
Background: Metal-on-metal arthroplasty may lead to elevated blood levels of chromium (Cr) and cobalt (Co). Since carcinogenic, mutagenic, and teratogenic effects of these metals have been suggested, there is concern of unfavorable pregnancy outcomes for women with this condition. After our first report (Fritzsche J. et al., Clin Orthop Relat Res 2012;470:2325-31), we present a second case with very high blood levels of these metals during pregnancy and the lactation period. Case: The 34-year-old patient had a unilateral metal-onmetal hip arthroplasty (prosthesis type DePuy ASR) for 7 years. The cause of the hip degeneration was unknown; bacterial infection was discussed. Metal blood levels were measured after the manufacturer had started a product recall. Two months before this pregnancy, she had extremely high chromium (47 lg/L; norm
MotherSafe Royal Hospital for Women, Randwick, New South Wales, Australia, 2School of Women’s and Children’s Health, University of New South Wales, New South Wales, Australia.
Background: Isotretinoin is a known teratogen and is prescribed for the treatment of severe cystic acne resistant to other forms of treatment. Because acne is a condition that affects young women of childbearing age, the risk for inadvertent pregnancy exposure is high. Unfortunately despite its known reproductive risks, women of reproductive age are still taking the drug (often for relatively trivial acne) and without appropriate counseling and contraception, resulting in exposed pregnancies at high risk of anomalies and other adverse outcomes. In Australia, isotretinoin can only be prescribed by a consultant physician or Dermatologist. Prescriptions are for a 1-month supply but come with a maximum of three repeats, meaning that it is possible for a woman to take the drug or initiate treatment several months after a negative pregnancy test. Methods: During the period 1 January 2009 to 30 April 2014, MotherSafe received 103 calls regarding concerns about isotretinoin exposure. Results: There were 10 calls regarding paternal isotretinoin exposure and 23 regarding topical exposures. In addition, there were two women who had previous stillbirths associated with isotretinoin use and were calling about retinoid exposures in a subsequent pregnancy. The mean age of all callers regarding retinoids was 30.17 years (range 15 to 45). Oral isotretinoin users were significantly younger (mean age 8.6 weeks (range 4–24 weeks). The majority of callers (52%) were consumers. Of the 68 calls regarding oral isotretinoin, 49 (72%) were regarding potential pregnancy exposures (including 12 or 18% where the specific reason for the call was given as considering termination of pregnancy). Five calls (7%) were
Published online 7 June 2014 in Wiley Online Library (wileyonlinelibrary.com). Doi: 10.1002/bdra.23258
C 2014 Wiley Periodicals, Inc. V
regarding exposure during breastfeeding and one caller wanted general information (i.e., not currently pregnant or planning pregnancy but considering her future reproductive options in relation to taking isotretinoin. On a positive note 13 women (19%) called regarding a future pregnancy (pregnancy planning). Of concern were the number of young women who did not receive appropriate counseling or use adequate contraception. Conclusion: This small series suggests a need to review Australian prescribing and dispensing guidelines and provide more education to both consumers and healthcare providers about appropriate management and the risks of this recognized teratogen.
2. Exposure to Isotretinoin in Pregnancy: An Ongoing Problem Maya Berlin,1 Natalia Dinavitser,1 Einat Gorelik,2 Dorit Nahlieli Dil,2 and Mati Berkovitch1 1
Clinical Pharmacology and Toxicology Unit, Teratogen Information Service, Assaf Harofeh Medical Center, Tzrifin, Israel, 2Pharmacovigilance and Drug Information Department, Pharmaceutical Division, Ministry of Health, Israel.
Background: Oral isotretinoin, a vitamin A analog, was first approved by United States Food and Drug Administration (FDA) in 1982 for the treatment of severe forms of acne. Upon approval, the drug was classified as teratogenic with an estimated 25% to 35% increased risk of congenital malformations and up to a 40% increased risk for spontaneous abortions. The first Pregnancy Prevention Program (PPP) was introduced in 1988 by FDA and Roche. In 2006, the FDA initiated the iPLEDGE, the most restricted, risk reduction program; even though, in the United States there are approximately 150 isotretinoinexposed pregnancies each year. The objective of this study was to assess the extent of isotretinoin exposed pregnancies, to characterize the exposed population, and to identify potential risk factors. Methods: Inspection of all cases in the Teratology Information Services (TIS) Zerifin between the years 2011 and 2014. Follow-up interviews were performed to women/physicians who contacted our TIS seeking advice about teratogen-risk counseling regarding oral retinoid exposure in pregnancy (including isotretinoin and acitretin). Additionally, the Adverse Drug Reaction database of Israeli Ministry of Health (MOH) was reviewed, as well as
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World Health Organization (WHO) database for reports of isotretinoin exposures during pregnancy worldwide. Results: Eighteen cases of isotretinoin and one case of acitretin exposures during pregnancy were identified in our database. Of those exposed, 10 (52.6%) women performed elective abortion after the counseling, 1 (5.3%) woman had spontaneous abortion, 2 (10.5%) women delivered healthy live babies, and 6 (31.6%) were lost to follow-up. Of the 13 women interviewed, none used two methods of contraception and only 4 used one method. During this period, the Israeli MOH did not receive any spontaneous reports regarding isotretinoin exposed pregnancies. The VigiLyze program of WHO identified 100 reports of isotretinoin and 1 report of acitretin exposures during pregnancy at the same time frame. Conclusion: In Israel, there is no active pregnancy retinoid exposure prevention program. We believe that this small scale study reveals only the tip of the iceberg, and dramatic change of approach is required. Following these findings, joint committee was assembled including all the TISs in Israel, Pharmacovigilance Department of the MOH and the Israeli Dermatology Organization to establish a national pregnancy prevention program.
3. Epidemiological Profile and Continuing Exposure to Retinoids by Women of Childbearing Age in Brazil Bruno Florentino Goldani,1,2 Luisa Grave Gross,1,2 Daniela Silva Santos,1,2 Luiza Metzdorf,1,2 Alberto Mantovani Abeche,2 Maria Teresa Vieira Sanseverino,2,3 Lavinia SchulerFaccini,2,3 and Fernanda Sales Luiz Vianna2,4
MEETING ABSTRACTS
conduct a survey and describe the profile of the use of systemic retinoids in women of childbearing age. In those with confirmed exposure assess, evaluate whether the observed anomalies are compatible with standard malformation embryopathy by retinoids; in topical exposures, to analyze the pregnancy outcome. Methods: Queries in SIAT were analyzed for the period 2003 to 2013 related to women of childbearing age who used any medications with retinoids during the periconceptional period and pregnancy. Results: Ninety-six records related to retinoids consultations were located. In 2013, five consultations occurred; 2013, 3; 2011, 8; 2010, 6; 2009, 6; 2008, 7; 2007, 10; 2006, 14; 2005, 15; 2004, 14, and 2003, 10. Of this total, 63 (65%) were consultations of pregnant women with use of oral retinoids, 14 (15%) were of women planning to become pregnant; 7 (7%) were of children born with birth defects where the mother has used any medication containing retinoid; 5 (5%) were related to research at the SIAT, and 7 (7%) were related to their reasons. Thirtynine (40%) were systemic exposures, and 13 (13%) were topical, and a query was for both routes of exposure. With data from 62% of pregnant women, we obtained an average age of 29.9 years. The evaluation of topical exposures is ongoing. Conclusion: Despite the retinoid-based drugs being contraindicated for pregnant women, our results demonstrate that exposure is still occurring in Brazil. This result indicates the need for more effective measures for effective contraception as for a better surveillance in the dispensation of these drugs.
1
Faculdade de Medicina, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brasil, 2Sistema Nacional de Informac¸~ ao sobre Agentes Teratog^enicos (SIAT), Porto Alegre, Brasil, 3Departamento de Genetica e Programa de PosGraduac¸~ ao em Genetica e Biologia Molecular, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brasil, 4Programa de Pos-Graduac¸~ ao em Epidemiologia, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brasil.
Background: It is known that systemic retinoid use for dermatological purposes has major teratogenic effects among the drugs on the market, and isotretinoin best known of them. With respect to topical use, although negative outcomes of malformations have been reported, this association is not proven by this type of exposure. In any situation, pregnancy is contraindicated, and women of childbearing age who take these drugs should undergo periodic pregnancy tests. However, SIAT Teratogen Information Service of Porto Alegre, Brazil, called Sistema Nacional de Informacoes Teratogenicas (SIAT), has received several reports of unintended pregnancies during retinoid treatments. The objectives of this study were to
4. Pregnancy Outcome following In Utero Exposure to Metformin: A Prospective Comparative Observational Study Oma Diav-Citrin,1,2 Salit Steinmetz-Shoob,3 Svetlana Shechtman,1 and Asher Ornoy2 1
The Israeli Teratology Information Service, Ministry of Health, Jerusalem, Israel, 2The Hebrew University Hadassah Medical School, Jerusalem, Israel, 3The Division of Clinical Pharmacy, the Hebrew University of Jerusalem, Israel.
Background: Metformin is a biguanide oral hypoglycemic agent used in the treatment of type 2 diabetes mellitus and in polycystic ovary syndrome (PCOS). Insulin is the mainstay of therapy for diabetes during pregnancy. Human first trimester (T1) pregnancy experience with metformin is limited. The primary objective of the study was to evaluate the rate of major anomalies after T1-metforminexposure among women with pregestational diabetes or PCOS. Methods: Pregnancies of callers who contacted the Israeli Teratology Information Service regarding metformin
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treatment during pregnancy between 2000 and 2013 were prospectively collected and followed up. The outcome was compared with a group of pregnant women with pregestational diabetes treated with insulin, and a comparison group of pregnant women counseled for non-teratogenic exposure (NTE), in a similar time frame. Results: A total of 171 T1-metformin-exposed pregnancies (120 for diabetes and 51 for PCOS) were followed up and compared, with 92 pregnancies of T1insulin-treated diabetic women, and 530 NTE pregnancies. The rate of congenital anomalies excluding genetic, cytogenetic, and spontaneously resolved cardiovascular anomalies was 4.3% (6/137) in the metformin group (PCOS 2/45 [4.4%], diabetes 4/92 [4.3%]), compared with 2.5% (2/79) in the insulin group, and 1.7% (9/ 519) in the NTE group. The differences were not statistically significant. However, the rate of all cardiovascular anomalies in the metformin (4/137 [2.9%]) group, was similar to the rate in the insulin group (2/79 [2.5%]), and higher compared with the NTE (0/519 [0%]) group, but not after excluding those that spontaneously resolved. There were no cases of caudal regression syndrome. The rate of Caesarean section deliveries was higher in both the metformin 69/132 (52.2%) and insulin 45/78 (57.7%) groups compared with the NTE group (123/485 [25.4%]). Conclusion: Metformin T1 exposure does not seem to be associated with an increased teratogenic risk.
5. Pregnancy Outcome following Maternal Exposure to Metformin: Preliminary Results of a Collaborative ENTIS and Motherisk Study A. Panchaud,1,2 D. Baud,3 T. Vial,4 N. Bernard,4 E. Amar,5 U. Winterfeld,2 L.E. Rothuizen,2 A. Dautriche,6 F. Beau-Salinas,7 A. Pistelli,8 H. Dunstan,9 Y.C. Kaplan,10 M. Kadioglu kov na a,12 G. Eleftheriou,13 G. Klinger,14 Duman,11 E. Ma 2 1 T. Buclin, C. Csajka, S. Hernandez-Diaz,15 and G. Koren16 1
School of Pharmaceutical Sciences, University of Geneva and Lausanne, Geneva, Switzerland, 2STIS and Division of Clinical Pharmacology, University Hospital, Lausanne, Switzerland, 3 Materno-Fetal and Obstetrics Research Unit, University Hospital, 1011 Lausanne, Switzerland, 4Pharmacovigilance Center of Lyon, Hospices Civils de Lyon, France, 5Registre des Malformations en Rhone Alpes (REMERA), Faculte Laennec, Lyon, France, 6 Pharmacovigilance Center of Dijon, CHU, Dijon, France, 7Pharmacovigilance Center of Tours, CHRU, Tours, France, 8Centro di Riferimento Regionale di Tossicologia Perinatale, Azienda Ospedaliero Universitaria Careggi, Florence, Italy, 9UKTIS, Regional Drug and Therapeutics Centre, Newcastle upon Tyne, United Kingdom, 10Izmir Katip Celebi University Faculty of Medicine Department of Pharmacology Teratology Information Service, Izmir, Turkey, 11Karadeniz Technical University, Faculty of Med-
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icine, Department of Pharmacology, Trabzon, Turkey, 12CZTIS, 3rd Faculty of Medicine, Charles University, Prague, Czech Republic, 13Poison Control, Bergamo, Italy, 14BELTIS Rabin Medical Center and Sackler School of Medicine, University of Tel-Aviv, Tel-Aviv, Israel, 15Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, 16The Motherisk Program, The Hospital for Sick Children, Toronto, Canada.
Background: Although a meta-analysis of eight controlled studies does not indicate an increased risk of major birth defects after first trimester exposure to metformin, the amount of evaluable pregnancies (N 5 172) is low, and its safety remains to be more fully established. Our aim was to assess more extensively the outcome of pregnancies exposed to metformin. Methods: Multicenter (n 5 9), observational prospective cohort study comparing pregnancy outcomes after exposure to metformin with a matched control group of patients not exposed to teratogenic agents or to any antidiabetic drugs. Data were collected by members of the European Network of Teratology Information Services (ENTIS) between 1995 and 2013. Motherisk data collection is still ongoing. Results: A population of 323 pregnant women exposed to metformin (median age [range]: 35 [19 – 47] years; gestational week at call: 10 [4 – 39]) were compared to 327 controls (median age [range]: 35 [21 – 45] years; gestational week at call: 9 [3 – 37]). A large majority of the patients in the exposed group had pregestational diabetes (71%). Major birth defects (after exclusion of chromosomal syndromes) were more frequent in the metformin group than in controls (7.6% versus 2.5%, unadjusted odds ratio 3.2; 95% CI: 1.3–9.2, p 5 0.005). Aside from the role of non-insulin dependent diabetes, an extensive search for other confounding factors is under way. The crude rates of spontaneous abortion (11.2% versus 6.2%, p 5 0.02) and medical pregnancy-terminations (3.1% versus 0.9%, p 5 0.05) were higher in the metformin group. Rates of premature birth (A rs4680, and ABCB1 G>A/T rs2032582 predict average pain score reported by Cohort 1; however, none of the independent variables on their own were statistically significant. In addition, gravidity and OPRM1 A>G rs1799971 predict average dose consumed by Cohort 1. Each variable was predictive on its own. Conclusion: Both clinical and genetic factors play a role in predicting effectiveness of codeine analgesia and dosage requirements. Differences in dose intake and pain relief seen across certain genetic polymorphisms suggest the need for dose adjustments or alternative forms of therapy in managing post-partum pain.
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nant woman is scarce, especially after introduction of a drug on the market. In the Netherlands, a national register called pREGnant, will be developed to monitor medication use during pregnancy and outcomes of the pregnancies. The primary focus is to establish a register with good quality data, useful to increase knowledge on medication use during pregnancy. Besides that, aspects like maintenance, privacy issues, and sharing data with third parties are another important part of the project. Methods: pREGnant is an initiative of the Teratology Information Service of the Netherlands Pharmacovigilance Centre Lareb in collaboration with the Pregnancy and Infant Development (PRIDE) Study. Pregnant women are enrolled around their first prenatal care visit through their midwife or gynecologist. The pregnant women are asked to fill out Web-based questionnaires at different moments in time ( 16 weeks, at 17, and 34 weeks gestational age and 2 and 6 months after delivery). Data will be collected on maternal health, medication use, the course and outcome of pregnancy, and the health of the child. Opportunities to link information available from existing registries, like the ‘The Netherlands Perinatal Registry’ (NPR), to the self-reported data will be explored. Different facets of the registry will be validated and evaluated. Inclusion methods, participation rate, as well as sources to obtain adequate data will be determined. The quality of data collected for drug exposure will be studied by comparing data in the Web-based questionnaires versus 2-months diaries versus pharmacy records. At last, data collection for outcomes will be validated by examining data obtained through pregnant women or Health Care Professionals or data from the NPR. Results: In April 2014, eight midwifery practices and two hospitals started electronic enrollment of the pregnant women. Four midwifery practices only hand out the leaflet about the registry, which describes how the woman herself can initiate participation through the pREGnant Web site. Conclusion: A national register will be developed and validated. The most optimal set-up to collect valid data in a labor and cost extensive way will be determined.
PHARMACOVIGILLANCE 60. Growth Percentile Webtool 59. Development of a National Register for Medication Use During Pregnancy in the Netherlands Bernke te Winkel,1 Saskia Vorstenbosch,1 and Eugene van Puijenbroek1,2
Haruna Sawada Feldman,1 Jennifer Zellner,1 Smriti Rao,1 David Kopald,1 Kenneth Lyons Jones,1 and Christina Chambers1–3 1
Netherlands Pharmacovigilance Centre Lareb, ‘s-Hertogenbosch, the Netherlands, 2University of Groningen, Department of Pharmacy, Pharmacotherapy and Pharmaceutical Care, Groningen, the Netherlands.
Department of Pediatrics, University of California San Diego, California, 2Department of Family and Preventive Medicine, University of California San Diego, San Diego, California, 3Clinical Translational Research Institute, University of California San Diego, San Diego, California.
Background: Information about medication use during pregnancy and the potential risk for the fetus and preg-
Background: A physical examination for fetal alcohol spectrum disorders (FASD) yields growth measurements
1
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that currently require the examiner to use graphs to plot the measurements to determine growth percentiles. The purpose of this project was to create a Webtool to calculate growth percentiles for measurements collected for a FASD prevalence study of 5- to 7-year-old children in the city of San Diego. Methods and Results: Several anthropometric measures were collected, including weight, height, head circumference, palpebral fissure lengths, inner canthal distance, and philtrum length. With the exception of philtrum length, growth curves were based on published references. An on-line Webtool was developed by creating formulas modeled after the CDC formulas for growth calculations on NutriStat (on EpiInfo). To reduce the error in reading the curves, three staff plotted the measurements for each line on the curve for each increment of age. To ensure the readings were consistent, percentiles were re-measured for any readings that differed by more than 0.5%. The average of the three values was then calculated. Using those plotted measurements, the standard deviation was calculated using the formula based on NutriStat, and subsequently the Z score was calculated. The Z table was used to identify percentiles. Webtool percentiles were validated against percentiles yielded from plotted graphs. As clinical concerns about growth are concentrated in those that are at or below the 10th centile or at or above the 90th centile, a lower margin of error was established for measurements in the lower and upper ranges. Conclusion: The Webtool has been a useful tool for calculating growth percentiles that are traditionally determined subjectively. More validation studies will be conducted as more data points are collected to verify the accuracy of the formulas. Additionally, the age range of the Webtool will be expanded. The Webtool is currently publicly available via: http://readysetgosandiego.org/resources/providers/. 61. Concordance of Information Reported by Health Care Professionals and Study Participants to a Teratogen Surveillance Study J.L. Richardson,1,2 A. Greenall,1 S. Stephens,1,2 L.M. Yates,1,3 and S.H.L. Thomas1,2 1
UK Teratology Information Service (UKTIS), Newcastle upon Tyne Hospitals NHS Foundation Trust, United Kingdom, 2Wolfson Unit of Clinical Pharmacology, Institute of Cellular Medicine, Newcastle University, United Kingdom, 3Northern Genetics Service, International Centre for Life, Newcastle upon Tyne Hospitals NHS Foundation Trust, United Kingdom.
Background: Teratogen surveillance studies are increasingly utilizing data from electronic patient medical records compiled of information provided by health care professio-
MEETING ABSTRACTS
nals (HCPs). However, the completeness and accuracy of the clinical details within these datasets is not fully understood. In 2009/10, UKTIS performed a prospective observational study of H1N1 exposure and management in pregnancy. In this study, questionnaires requesting the same demographic/clinical details for each participant were collected from both HCPs (mainly general practitioners) and study participants (SPs). This analysis aims to test the concordance of the information reported. Methods: To test the completeness of data provision, we compared the HCP and SP response rates to each element of the questionnaire using McNemar’s chi squared analysis of paired data. Where demographic/clinical details had been provided by both responders, we tested the level of agreement in the data provided using Cohen’s kappa statistic. Results: Information was provided by both HCPs and SPs for reported pregnancies at study enrollment (n 5 664), pregnancy outcome (n 5 371), and at 6-month infant outcome (n 5 225). The analysis showed that a significantly higher number of SPs provided information in their reports concerning residential location, occupation, ethnicity, body mass index (BMI), tobacco, alcohol or recreational drug use, gravidity, family history of congenital malformations and genetic conditions, medication use, pregnancy outcome, and infant birth weight. A significantly higher number of HCPs provided information concerning pre-existing maternal medical conditions and the gestational age at pregnancy outcome. Where demographic/ clinical details were provided by both HCPs and SPs there was a poor level of agreement regarding maternal BMI, periconceptual tobacco and alcohol use, family history of congenital malformation and genetic condition, medication exposure, pregnancy complications, neonatal problems, presence of congenital malformation, and neurodevelopmental impairment. Conclusion: Our findings indicate that some details relevant to the assessment of teratogenic risk may be unreported, or potentially inaccurately reported by HCPs. As the majority of the HCP responders to the H1N1 study were general practitioners, this analysis may raise some concerns with the use of data collected from U.K. primary care record datasets in teratogen surveillance/post-marketing pregnancy safety studies. 62. Participant Recruitment to the PROTECT Pregnancy Study; a Non-interventional, Prospective Study of Self-Reported Medication Use and Obstetric Outcomes as Provided by a Cohort of Pregnant Women J.L. Richardson,1,2 S. Stephens,1,2 S.H.L. Thomas,1,2 A. LatosBielenska,3 A. Jamry-Dziurla,3 L.T.W. de Jong-van den Berg,4 P. Zetstra-van der Woude,4 M. Laursen,5 N. Dreyer,6 V. Hliva,6 S. Mt-Isa,7 and S.C.F. Blackburn6 1
UK Teratology Information Service, Newcastle upon Tyne Hospitals NHS Foundation Trust, United Kingdom, 2Wolfson Unit of
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Clinical Pharmacology, Institute of Cellular Medicine, Newcastle University, United Kingdom, 3Department of Medical Genetics, Poznan University of Medical Sciences, Poland, 4Department of Pharmacy, University of Groningen, Netherlands, 5Department of Data Delivery and Medicinal Product Statistics, National Institute for Health Data and Disease Control, Denmark, 6Department of Real-World and Late Phase Research, Quintiles, 7Imperial Clinical Trials Unit, Imperial College London, United Kingdom.
Background: Some teratogen surveillance techniques can be costly, particularly in researcher time, and occasionally confounded by a lack of important maternal information regarding concomitant risk factors such as over-thecounter or herbal medication use. Prospective selfprovision of data by pregnant women could address some of these issues providing a sufficient number of study participants can be enrolled without the introduction of alternative limitations. The PROTECT Pregnancy Study was performed as a Web-based pilot investigation of medication use and obstetric outcomes self-reported by pregnant women. It was carried out in four countries: Denmark (DK) the Netherlands (NL), Poland (PL), the United Kingdom (U.K.). A primary aim was to assess the feasibility of data collection from self-enrolled participants. We therefore used direct-to-participant advertisement methods which did not require health care professional input. Here, we compare the costs of advertisement methods used, and the demographic/clinical characteristics, and participation practices of the study sub-populations they enrolled. Methods: Advertisement methods included the postal mailing/placement of leaflets in clinical areas, online social media group campaigns, adverts in magazines, on television and websites, and via e-mails sent from online parenting/pregnancy clubs. In this analysis means were compared though one-way analysis of variance, incidences with Pearson’s chi-squared. Results: A total of 2,521 participants self-enrolled in the study. The total cost of advertisement was e40,958. Significant international differences in mean cost/participant were observed (DK e12.66, NL e23.57, PL e20.53, UK e13.07, p < 0.001). Of the total recruited participants 2065 provided information relating to the advertisement methods which notified them of the study. Significant differences in participant demographic/clinical characteristics and participation practices were observed between those recruited through the various advertisement methods. These included differences in the incidence of maternal age 35 years, body mass index 25, first trimester study enrollment, prima-gravidity, university education, alcohol use, and gestational follow-up/pregnancy outcome data provision. Conclusion: These findings suggest that direct-toparticipant advertisement of a self-completed Web-based teratogen surveillance study may require a substantial financial resource, and costs may vary by location. Use of different direct-to-participant advertisement methods may also impact
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upon the demographic/clinical characteristics and participation practices of a study population. This research received support from the IMI-JU through the PROTECT project. 63. Use of Antiepileptic Drugs in Women of Childbearing Age and during Pregnancy: Critical Appraisal of Information Provided by the Summary of Product Characteristics Ursula Winterfeld,1 Verena Gotta,1 Laura E. Rothuizen,1 Alice Panchaud,1,2 Andrea O. Rossetti,3 and Thierry Buclin1 1
Swiss Teratogen Information Service et Division de pharmacologie clinique, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland, 2Section des sciences pharmaceutiques, Faculte des sciences, Universite de Gene`ve, Universite de Lausanne, Lausanne, Switzerland, 3Departement des Neurosciences Cliniques, Centre Hospitalier Universitaire Vaudois (CHUV) et Universite de Lausanne, Lausanne, Switzerland.
Background: Health care professionals regularly read the summary of product characteristics (SmPC) as one of different sources of information on the risks of drug use in women of childbearing age and during pregnancy. The aim of this work is to present an overview of the teratogenic potential of various antiepileptic drugs and to compare these data with the information provided by the SmPCs. Methods: We conducted a literature review on the teratogenic risks of 19 antiepileptic agents. We compared the results with the information on use in women of childbearing age and during pregnancy provided by the SmPCs of 38 commercial products available in Switzerland and Germany. Results: The teratogenic risk is discussed in all SmPCs. Quantification of the risk for birth defects and numbers of published human exposed pregnancies are mostly missing. Reproductive safety information in SmPCs show poor concordance with risk levels reported in the literature. Recommendations concerning the need to monitor plasma levels and possibly perform dose adjustments during pregnancy to prevent treatment failure are missing in five Swiss and two German SmPCs. Conclusion: The information regarding use in women of childbearing age and during pregnancy provided by the SmPCs is heterogeneous and poorly reflects the current state of knowledge. Regular updates of SmPCs are warranted in order for these documents to be of reliable use for health care professionals. 64. List of the Drugs and Herbal Medicines Consumed by Brazilian Women During Pregnancy A. Salazar-Granara,1,2 M. Galvan,1 M.T.V. Sanseverino,1 A.M. Abeche,1 and L. Schuler-Faccini1–3 1
Brazilian Teratogen Information Service (SIAT), Hospital de Clınicas de Porto Alegre, Brazil, 2Center of Traditional Medicine
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and Pharmacology of the San Martin de Porres University, Peru, 3 Genetics Department of the Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
Background: The use of drugs and herbal medicines during pregnancy should be approached with caution, due to the potential deleterious effects such as miscarriage and teratogenicity, among others. Here, we establish a list of the drugs and medicinal plants used by pregnant Brazilian women who contacted the Brazilian Teratology Information Service. Methods: We analyzed 9023 clinical records from the Brazilian Teratogen Information Service (SIAT, http://gravidez-segura.org/) in Porto Alegre, Brazil, from 1990 to 2012. Results: According to the Anatomical Therapeutic Chemical (ATC) classification system, 39 groups of drugs have been registered. The 10 most common drugs are: (1) benzodiazepine (12%); (2) antiobesity drugs (10%); (3) non-steroid anti-inflammatories (9%); (4) antipsychotics (6%); (5) diuretics (6%); (6) sex hormones (6%); (7) sympathomimetics (5%); (8) antidepressants (4%); (9) antihistamines (4%); and (10) vitamins (4%). By contrast, a total of 145 herbal medicines have been registered. The 10 most used herbals are: (1) Rhamnus purshiana (Bearberry) (17%); (2) Centella asiatica (Centela) (10%); (3) Passiflora alata (Passionfruit) (10%); (4) Cassia angustifolia (Senna) (10%); (5) Ginkgo biloba (Ginkgo) (7%); (6) Fucus vesiculosis (Seaweed) (5%); (7) Mentha pipireta (Peppermint) (5%); (8) Aesculus hippocastanum (Horse-chestnut) (5%); (9) Garcinia cambogia (Gambooge) (4%); and (10) Piper methysticum (Kava) (4%). Conclusion: Considering the U.S. Food and Drug Administration risk categories, we observed drugs classified as X (benzodiazepine, sex hormones), D (non-steroids antiinflammatory, antipsychotics, sympathomimetic, and antidepressant), and C (antiobesity, antihistamine, and diuretic). On the other hand, according to the World Health Organization’s Medicinal Plants Monography, the use during pregnancy of Rhamnus purshiana, Ginkgo biloba, and Mentha pipireta, has been contraindicated; and for the four remaining plants (Passiflora alata, Centella asiatica, Aesculus hippocastanum, and Piper methysticum) it is stated that there is no information available concerning the teratogenic or non-teratogenic effects on pregnancy. In relation to Cassia angustifolia, Fucus vesiculosis, and Garcinia cambogia, we were unable to find any information. This database of common drug and herbal products used by pregnant women is, therefore, of great importance in providing appropriate information for doctors and patients in Brazil. 65. Clinical Characteristics of Pregnancies in Brazilian Women Involving the Use and Non-use of Medicinal Herbs A. Salazar-Granara,1,2 M. Galvan,1 M.T.V. Sanseverino,1 A.M. Abeche,1 and L. Schuler-Faccini1–3 1
Brazilian Teratogen Information Service (SIAT), Hospital de Clınicas de Porto Alegre, Brasil, 2Center of Traditional Medicine
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and Pharmacology of the San Martin de Porres University, Peru, Genetics Department of the Universidade Federal do Rio Grande do Sul, Porto Alegre, Brasil.
3
Background: The aim of this study was to compare the clinical characteristics of the pregnancies in Brazilian women involving the use and non-use of herbal drugs. Methods: We analyzed 9023 clinical records from the Brazilian Teratogen Information Service (SIAT, http://gravidez-segura.org/) in Porto Alegre, Brazil, from 1990 to 2012. One hundred clinical records were randomly selected from pregnant women who used herbal drugs, and the same procedure was done for the control group. Results: The mothers involved in the study resided mainly in the South region of Brazil (63% herbal users, and 59% non-herbal group). The most common maternal education was “high school completed, with 40% and 44%, respectively; followed by “university completed,” with 36% and 20%. Women over 34 years were more frequent in the herbal consumers group (24% vs. 18%) and teenage mothers (4 births) (12% vs. 2%) (Fisher test, IC 95%, p < 0.02) were significantly higher in the herbal consumers. Previous miscarriage occurred in 29% of herbal users and 21% of non-users. Addictive maternal habits were present equally in both groups (31% and 32%, respectively). The concomitant use of two or more medications was 80% and 53% (Fisher test, IC 95%, p < 0.004). Most drug and herb exposure occurred during the first trimester (65% and 36%); followed by the second trimester (29% and 48%); and few in the third trimester (6% and 15%). Conclusion: In our sample, pregnant women consuming herbal products tend to be older and with higher education than non-herbal users. Correlated to the advanced maternal age, as expected, the number of previous pregnancies and miscarriages are as well increased in the herbal group. 66. Birth Outcomes for the Pregnancies of Brazilian Women Who Use Herbal Drugs A. Salazar-Granara,1,2 M. Galvan,1 M.T.V. Sanseverino,1 A.M. Abeche,1 and L. Schuler-Faccini1–3 1
Brazilian Teratogen Information Service (SIAT), Hospital de Clınicas de Porto Alegre, Brasil, 2Center of Traditional Medicine and Pharmacology of the San Martin de Porres University, Peru, 3 Genetics Department of the Universidade Federal do Rio Grande do Sul, Porto Alegre, Brasil.
Background: The aim of this study was to compare the clinical characteristics of the birth outcomes of pregnant Brazilian women who used herbal drugs.
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Methods: We analyzed 9023 clinical records from the Brazilian Teratogen Information Service (SIAT, http://gravidez-segura.org/) in Porto Alegre, Brazil, from 1990 to 2012. Fifty clinical records were randomly selected from pregnant women who used herbal drugs, and 50 for the non-users of herbal drugs. Results: The pregnancy results were: miscarriage, 11% versus 5%; stillbirth, 2% and 7%; live birth, 83% and 88%; in the herbal and non-herbal group, respectively. Cesarean births accounted for 67% and 62%, respectively. Male sex was 60% and 48%. The Apgar newborn scores were similar in both groups. Pre-term births (less than 38 weeks) occurred in 30% and 40%; correspondingly, in the same way, the postterm births (more than 41 weeks) were 4% and 7%; also, the low birth weight (between 1500 and 2500 g) were 14% and 12%, respectively, and, macrosomic (more than 4000 g) were 7% for both. Small for gestational age was observed in 28% and 11%, correspondingly. Congenital anomalies were present in 12% in the herbal group and 42% in the non-herbal group. For all the comparisons, it was applied the Fisher exact test and the result was non-significant. Conclusion: In the sample studied, the adverse outcomes were less frequent in the herbal exposed group compared to the non-herbal users.
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screen positive were selected to receive a comprehensive FASD evaluation. Logistic regression models were constructed to determine if the PEDS was predictive of an FASD classification. Results: There were 178 children with completed evaluations. Of these, 35 received an FASD classification. Three children were classified with fetal alcohol syndrome (FAS), 25 with partial fetal alcohol syndrome (pFAS), and 7 with a preliminary classification of alcohol-related neurodevelopmental disorder (ARND). Among the 35 who were classified as FASD, 7 screened positive on both PEDS and growth, 7 were selected as random controls, 11 screened positive on growth only, and 10 screened positive on PEDS only. Screening positive on PEDS was not predictive of an FASD classification (p 5 0.85). When comparing each of the FASD classification groups to the no FASD classification group, there were no significant differences (FAS, p 5 0.56; pFAS, p 5 0.88; and ARND, p 5 0.70). Conclusion: While the PEDS was not predictive of FASD, it did identify 29% of the children who were subsequently classified with an FASD but did not screen positive on growth. Thus, although the PEDS was not specific as a screening tool, it improved sensitivity for identifying children with an FASD. The inclusion of additional completed evaluations may shed more light on the utility of the PEDS in screening for FASD.
67. Utility of PEDS for a FASD Prevalence Study in a School-Based Population
ENVIRONMENTAL DRUGS OF ABUSE AND ALCOHOL Haruna Sawada Feldman,1 Jennifer Zellner,1 Kenneth Lyons Jones,1 and Christina Chambers1–3 1
Department of Pediatrics, University of California San Diego, San Diego, California, 2Department of Family and Preventive Medicine, University of California San Diego, San Diego, California, 3Clinical Translational Research Institute, University of California San Diego, San Diego, California.
Background: The Parents’ Evaluation of Developmental Status (PEDS) questionnaire screens for developmental and behavioral problems in children, including expressive and receptive language, fine and gross motor skills, socialemotional functioning, behavioral concerns, and school performance. The objective of this cross-sectional analysis was to determine if the PEDS used as a screening tool is effective in identifying children with fetal alcohol spectrum disorder (FASD). Methods: The city of San Diego FASD prevalence study included children in the first grade from selected schools for the 2012/2013 and 2013/2014 academic years. Two screening methods (any growth measurements 25th centile, and two or more domains positive on the PEDS) were used to determine children at risk for a potential FASD classification. Children who screened positive and a random sample of children who did not
68. Utility of PEDS for a FASD Prevalence Study in a SchoolBased Population Haruna Sawada Feldman,1 Jennifer Zellner,1 Kenneth Lyons Jones,1 and Christina Chambers1–3 1
Department of Pediatrics, University of California San Diego, San Diego, California, 2Department of Family and Preventive Medicine, University of California San Diego, San Diego, California, 3Clinical Translational Research Institute, University of California San Diego, San Diego, California.
Background: The Parents’ Evaluation of Developmental Status (PEDS) questionnaire screens for developmental and behavioral problems in children, including expressive and receptive language, fine and gross motor skills, socialemotional functioning, behavioral concerns, and school performance. The objective of this cross-sectional analysis was to determine if the PEDS used as a screening tool is effective in identifying children with Fetal Alcohol Spectrum Disorders (FASD). Methods: The city of San Diego FASD prevalence study included children in the first grade from selected schools for the 2012/2013 and 2013/2014 academic years. Two screening methods (any growth measurements 25th centile,
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and two or more domains positive on the PEDS) were used to determine children at risk for a potential FASD classification. Children who screened positive and a random sample of children who did not screen positive were selected to receive a comprehensive FASD evaluation. Logistic regression models were constructed to determine if the PEDS was predictive of an FASD classification. Results: There were 178 children with completed evaluations. Of these, 35 received an FASD classification. Three children were classified with fetal alcohol syndrome (FAS), 25 with partial fetal alcohol syndrome (pFAS), and 7 with a preliminary classification of alcohol-related neurodevelopmental disorder (ARND). Among the 35 who were classified as FASD, 7 screened positive on both PEDS and growth, 7 were selected as random controls, 11 screened positive on growth only, and 10 screened positive on PEDS only. Screening positive on PEDS was not predictive of an FASD classification (p 5 0.85). When comparing each of the FASD classification groups to the No FASD Classification group, there were no significant differences (FAS, p 5 0.56; pFAS, p 5 0.88; and ARND, p 5 0.70). Conclusion: While the PEDS was not predictive of FASD, it did identify 29% of the children who were subsequently classified with an FASD but did not screen positive on growth. Thus, although the PEDS was not specific as a screening tool, it improved sensitivity for identifying children with an FASD. The inclusion of additional completed evaluations may shed more light on the utility of the PEDS in screening for FASD. 69. Update on Teratogenic Infections: Effects on Mental Disorders Asher Ornoy
1
nal exposure to valproic acid during pregnancy is associated with a four- to five-fold increase in ASD, equally affecting about 5% of male and female children. Maternal rubella was known for decades to be associated with an increased risk of ASD, but recently influenza and fever, as well as other maternal infections during pregnancy, have also been associated with an increased rate of ASD. In addition, an increased rate of schizophrenia among the offspring was demonstrated following maternal rubella, toxoplasmosis, and influenza infections during pregnancy, as well as (bacterial) urinary tract infections. Conclusion: It is still unknown whether these associations result from the inflammatory processes in the fetal brain, from fever, or is related to the specific effects of the infective agents. Among suggested mechanisms are elevated inflammatory cytokines and oxidative stress affecting the brain. Recent studies on infected pregnant animals have also shown an increase in behavioral changes in the adult offspring. This increase in mental disorders resulting from teratogenic exposures in pregnancy is in line with other problems, first appearing in children or young adults, but originating from intrauterine insults during embryonic/fetal development. An example is the "metabolic syndrome" characterized by overweight, hypertension, cardiovascular disease, and type 2 diabetes, commonly developing in offspring of diabetic mothers at adulthood. 70. Folic Acid Supplementation for the Prevention of Birth Defects: The Experience of the Teratology Information Service of Padova a,1 Marco Braggion,1 Elena Di Matteo Cassina,1 Marta Don 1 Gianantonio, and Maurizio Clementi1
1
1
Background: The deleterious effects of most commonly known teratogenic infectious agents, e.g., rubella, cytomegalovirus (CMV), Toxoplasma, herpes, and varicella zoster, are well established. It is also known that a dramatic decrease in the rate of these, as well as of other infections (i.e. rubella, varicella zoster), can be achieved by proper immunization. Methods: Recent phase 2 clinical trials with the CMV gB/Mf59 and the DNA TransVax vaccines have demonstrated a 50% efficacy, giving some hope for effective vaccination. In spite of the well-known damaging effects of these infections on the fetal brain, causing serious neurodevelopmental disorders, knowledge on their possible effects on mental diseases was poor. Results: Studies in animals and man have shown an association between teratogenic exposures in pregnancy and autistic spectrum disorder (ASD). For example, mater-
Background: A deficiency of folic acid in early pregnancy is associated with an increased risk of congenital malformations, especially neural tube defects. A public health campaign for the promotion of the periconceptional consumption of folic acid started few years ago in Italy. Methods: To evaluate the effectiveness of the campaign, we conducted an observational study assessing women who contacted the Teratology Information Service (TIS) of Padova during their pregnancy. After the expected delivery date, women or their physicians were contacted for a follow-up telephone interview to collect information regarding the outcome of their pregnancy and the use of folic acid in their periconceptional period. Pregnancies with the last menstrual period between 1 January 2007 and 31 December 2012 were included in the study. The sample was divided into two groups: women who started
Hebrew University Hadassah Medical School and Israeli Teratogen Information Service, Ministry of Health, Jerusalem, Israel.
Teratology Information Service, Clinical Genetics Unit, Department of Women’s and Children’s Health, University of Padova, Padova, Italy.
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the folic acid supplementation before conception, and women who assumed folic acid only after confirmation of pregnancy. Results and Discussion: A total of 2473 women contacted the TIS of Padova and were available for the follow-up interview; 174 women (7%) were counseled for antiepileptic drugs exposure. Eighty-seven percent of these answered to questions regarding the intake of folic acid during pregnancy. Most of the women took folic acid during pregnancy, with a slight increase from 2007 to 2012 (from 87.1% to 94.8%) and without significant differences between the two subgroups. The supplementation was more likely taken before conception by women treated with antiepileptic drugs (22.8% vs. 11.7%, p 5 0.001). This analysis suggests that the rate of women assuming folic acid supplementation before conception is still low, even in a highly selected and sensitized population such as the one we studied. The importance of the periconceptional folic acid supplementation does not appear to have been adequately understood also by patients affected by chronic diseases requiring treatment with antiepileptic drugs, many of which interfere with the folate metabolism and increase the risk of neural tube defects and other congenital malformations. These results may be due to the high rate of unplanned pregnancies, the poor compliance to folic acid supplementation (which is often long-term) and the lack of a preconception counseling. 71. Second Case Report of Very High Chromium and Cobalt Levels in Pregnancy due to Metal-on-Metal Hip Arthroplasty M. Oppermann,1 C. Borisch,1 C. Weber-Schoendorfer,1 and C. Schaefer1 1
Pharmakovigilanz- und Beratungszentrum f€ ur Embryonaltoxikologie, Charite Universit€ atsmedizin, Spandauer Damm, Berlin, Germany.
Background: Metal-on-metal arthroplasty may lead to elevated blood levels of chromium (Cr) and cobalt (Co). Since carcinogenic, mutagenic, and teratogenic effects of these metals have been suggested, there is concern of unfavorable pregnancy outcomes for women with this condition. After our first report (Fritzsche J. et al., Clin Orthop Relat Res 2012;470:2325-31), we present a second case with very high blood levels of these metals during pregnancy and the lactation period. Case: The 34-year-old patient had a unilateral metal-onmetal hip arthroplasty (prosthesis type DePuy ASR) for 7 years. The cause of the hip degeneration was unknown; bacterial infection was discussed. Metal blood levels were measured after the manufacturer had started a product recall. Two months before this pregnancy, she had extremely high chromium (47 lg/L; norm
