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In November 2019, section 4.6 of the ondansetron Summary of Product Characteristics (SmPC) was revised by the European Medicines Agency. It explicitly states, 'ondansetron should not be used during the first trimester of pregnancy' (Ondansetron, SmPC [accessed 8 July 2020]. [Extracted from the article]

Background: Valproate is a first-line antiepileptic agent and is also used in the treatment of bipolar disorder and migraine. It is a known human teratogen. The objective of the study was to evaluate the teratogenic risk of valproate.Methods: All callers who contacted the Israeli Teratology Information Service (TIS) between 1994 and 2004 for information about gestational exposure to valproate were enrolled in the study. After the expected date of delivery, these women were followed up by telephone interview about their pregnancy outcome using a structured questionnaire. Data obtained from women who contacted the TIS about valproate exposure during pregnancy were then compared with data obtained from callers who were counselled for nonteratogenic exposures over the same timeframe. The main outcome measure was the rate of major congenital anomalies.Results: The outcomes of 154 valproate-exposed pregnancies (96.1% at least in the first trimester) were compared with those of 1315 pregnancies of women in the TIS database who were counselled for nonteratogenic exposures. The rate of major anomalies (some multiple) in the valproate group exposed in the first trimester was higher compared with controls after exclusion of genetic or cytogenetic anomalies (8 of 120 [6.7%] vs 31 of 1236 [2.5%], p = 0.018, relative risk [RR] = 2.66, 95% CI 1.25, 5.65). There were no cases of neural tube defect in the valproate-exposed group. Five of the eight major anomalies in the valproate group were cardiovascular, two of eight were mentally retarded, two of five male infants with major anomalies had hypospadias and three of eight were suspected of having fetal valproate syndrome. A daily dose > or =1000 mg was associated with the highest teratogenic risk (7 of 32 [21.9%] vs 31 of 1236 [2.5%], RR = 8.72, 95% CI 4.16, 18.30). In the subgroup exposed to polytherapy there was a 4-fold increase in the rate of major anomalies compared with controls. All major anomalies were in the group treated for epilepsy.Conclusion: When valproate treatment cannot be avoided in the first trimester of pregnancy, the lowest effective dose should be prescribed, preferably as monotherapy, to minimize its teratogenic risk. [ABSTRACT FROM AUTHOR]

On January 12, 2024 the safety committee of the European Medicines Agency (EMA) recommended precautionary measures over a potential risk of neurodevelopmental disorders in children born to men treated with valproate. These new measures recommend patient supervision by a specialist in the management of epilepsy, bipolar disorder, or migraine. In the United Kingdom, the Medicines and Healthcare products Regulatory Agency (MHRA) issued a far more stringent precaution, warning against prescribing valproate to anyone under 55 years of age. We, members of the European Network of Teratology Information Services (ENTIS) and the Organization of Teratology Information Specialists (OTIS), believe that the EMA and MHRA warnings were premature. We are of the opinion that the underlying scientific data do not convincingly substantiate the inference of a paternally mediated risk from valproate to children, much less to an extent that justifies these far-reaching recommendations., (© 2024 Wiley Periodicals LLC.)

Objectives: Glucagon-like peptide 1 receptor agonists (GLP1-RA) are indicated for the treatment of type 2 diabetes and more recently for weight loss. The aim of this study was to assess the risks associated with GLP1-RA exposure during early pregnancy., Design: This multicentre, observational prospective cohort study compared pregnancy outcomes in women exposed to GLP1-RA in early pregnancy either for diabetes or obesity treatment with those in two reference groups: (1) women with diabetes exposed to at least one non-GLP1-RA antidiabetic drug during the first trimester and (2) a reference group of overweight/obese women without diabetes, between 2009 and 2022., Setting: Data were collected from the databases of six Teratology Information Services., Participants: This study included 168 pregnancies of women exposed to GLP1-RA during the first trimester, alongside a reference group of 156 pregnancies of women with diabetes and 163 pregnancies of overweight/obese women., Results: Exposure to GLP1-RA in the first trimester was not associated with a risk of major birth defects when compared with diabetes (2.6% vs 2.3%; adjusted OR, 0.98 (95% CI, 0.16 to 5.82)) or to overweight/obese (2.6% vs 3.9%; adjusted OR 0.54 (0.11 to 2.75)). For the GLP1-RA group, cumulative incidence for live births, pregnancy losses and pregnancy terminations was 59%, 23% and 18%, respectively. In the diabetes reference group, corresponding estimates were 69%, 26% and 6%, while in the overweight/obese reference group, they were 63%, 29% and 8%, respectively. Cox proportional cause-specific hazard models indicated no increased risk of pregnancy losses in the GLP1-RA versus the diabetes and the overweight/obese reference groups, in both crude and adjusted analyses., Conclusions: This study offers reassurance in cases of inadvertent exposure to GLP1-RA during the first trimester of pregnancy. Due to the limited sample size, larger studies are required to validate these findings., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Introduction and Objective: The ConcePTION project aims to improve the way medication use during pregnancy is studied. This includes exploring the possibility of developing a distributed data processing and analysis infrastructure using a common data model that could form a foundational platform for future surveillance and research. A prerequisite would be that data from various data access providers (DAPs) can be harmonised according to an agreed set of standard rules concerning the structure and content of the data. To do so, a reference framework of core data elements (CDEs) recommended for primary data studies on drug safety during pregnancy was previously developed. The aim of this study was to assess the ability of several public and private DAPs using different primary data sources focusing on multiple sclerosis, as a pilot, to map their respective data variables and definitions with the CDE recommendations framework., Methods: Four pregnancy registries (Gilenya, Novartis; Aubagio, Sanofi; the Organization of Teratology Information Specialists [OTIS]; Aubagio, Sanofi; the Dutch Pregnancy Drug Register, Lareb), two enhanced pharmacovigilance programmes (Gilenya PRIM, Novartis; MAPLE-MS, Merck Healthcare KGaA) and four Teratology Information Services (UK TIS, Jerusalem TIS, Zerifin TIS, Swiss TIS) participated in the study. The ConcePTION primary data source CDE includes 51 items covering administrative functions, the description of pregnancy, maternal medical history, maternal illnesses arising in pregnancy, delivery details, and pregnancy and infant outcomes. For each variable in the CDE, the DAPs identified whether their variables were: identical to the one mentioned in the CDE; derived; similar but with a divergent definition; or not available., Results: The majority of the DAP data variables were either directly taken (85%, n = 305/357, range 73-94% between DAPs) or derived by combining different variables (12%, n = 42/357, range 0-24% between DAPs) to conform to the CDE variables and definitions. For very few of the DAP variables, alignment with the CDE items was not possible, either because of divergent definitions (1%, n = 3/357, range 0-2% between DAPs) or because the variables were not available (2%, n = 7/357, range 0-4% between DAPs)., Conclusions: Data access providers participating in this study presented a very high proportion of variables matching the CDE items, indicating that alignment of definitions and harmonisation of data analysis by different stakeholders to accelerate and strengthen pregnancy pharmacovigilance safety data analyses could be feasible., (© 2023. The Author(s).)

Purpose/background: Trazodone is indicated for the treatment of major depressive disorder, but more frequently prescribed off-label at lower doses for insomnia in women of childbearing age. The aim of this study was to assess the risks linked to trazodone exposure during pregnancy for which limited safety data are available., Methods/procedures: This multicenter, observational prospective cohort study compared pregnancy outcomes in women exposed to trazodone in early pregnancy against those in a reference group of women exposed to a selective serotonin reuptake inhibitors (SSRIs) between 1996 and 2021., Findings/results: The sample included 221 trazodone and 869 SSRI-exposed pregnancies. Exposure to trazodone in the first trimester was not associated with a significant difference in the risk of major congenital anomalies (trazodone [1/169, 0.6%]; SSRI [19/730, 2.6%]; adjusted odds ratio, 0.2; 95% confidence interval, 0.03-1.77). The cumulative incidences of live birth were 61% and 73% in the trazodone and reference group, respectively (25% vs 18% for pregnancy loss and 14% vs 10% for pregnancy termination). Trazodone exposure was not associated with a significantly increased risk of pregnancy termination and pregnancy loss. The rate of small for gestational age infants did not differ between the groups., Implications/conclusions: This study did not reveal a significant difference in the risk of major congenital anomalies after first trimester exposure to trazodone, compared with SSRI exposure. Although this study is the largest so far, these results call for confirmation through further studies., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Ondansetron is an effective antiemetic that is being widely used as a second-line treatment option for severe nausea and vomiting of pregnancy in accordance with clinical guidelines. The safety of ondansetron during pregnancy has-following publication of controversial and seemingly contradictory results-been subject to considerable academic turmoil, specifically with respect to the risk of congenital cardiac malformations and oral cleft. In July 2019, the European Medicines Agency (EMA) Pharmacovigilance Risk Assessment Committee (PRAC) released an updated, comprehensive assessment report on the use of ondansetron in the first trimester. The ensuing Summary of Product Characteristics (SmPC) was updated in November 2019 with important changes to section on "Fertility, pregnancy and lactation." The SmPC now states that ondansetron should not be used in the first trimester of pregnancy. ENTIS, The European Network of Teratology Information Services, believes that the implementation of this regulatory step-which has important clinical consequences-is insufficiently substantiated and is not serving the interest of pregnant women with severe nausea and vomiting. Herein, we discuss the underlying evidence and argue the case against the EMA decision., (© 2020 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

Artificial intelligence (AI) is defined as the ability of machines to perform tasks that are usually associated with intelligent beings. Argument and debate are fundamental capabilities of human intelligence, essential for a wide range of human activities, and common to all human societies. The development of computational argumentation technologies is therefore an important emerging discipline in AI research 1 . Here we present Project Debater, an autonomous debating system that can engage in a competitive debate with humans. We provide a complete description of the system's architecture, a thorough and systematic evaluation of its operation across a wide range of debate topics, and a detailed account of the system's performance in its public debut against three expert human debaters. We also highlight the fundamental differences between debating with humans as opposed to challenging humans in game competitions, the latter being the focus of classical 'grand challenges' pursued by the AI research community over the past few decades. We suggest that such challenges lie in the 'comfort zone' of AI, whereas debating with humans lies in a different territory, in which humans still prevail, and for which novel paradigms are required to make substantial progress.

The objective of the study was to evaluate the rate of major congenital anomalies after first trimester exposure to ondansetron for nausea and vomiting of pregnancy (NVP). The design is a prospective, comparative, observational cohort study, performed at the Israeli Teratology Information Service between 2010 and 2014. Follow-up was obtained for 195 ondansetron-exposed, 110 metoclopramide-exposed, and 778 pregnancies with non-teratogenic exposure (NTE). The overall rate of major anomalies did not significantly differ between the groups [4/200 = 2.0 % (ondansetron), 1/109 = 0.9 % (metoclopramide), and 13/731 = 1.8 % (NTE)]. All the anomalies in both the ondansetron and metoclopramide groups, and 6/13 anomalies in the NTE group, were cardiac septal defects most of which spontaneously resolved. Both ondansetron (adjHR = 0.29, 95 % CI 0.10-0.80) and metoclopramide (adjHR = 0.27, 95 % CI 0.08-0.86) were associated with lower miscarriage rate compared to NTE. Based on the present study, ondansetron during pregnancy is not associated with an increased risk for overall major anomalies, nor for clinically important cardiac defects. It may be a reasonable alternative for women with severe NVP who do not respond to first line medications., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: To evaluate the rate of major anomalies after first trimester (T1)-metformin exposure., Design: Comparative, observational cohort study done at the Israeli Teratology Information Service between 2000 and 2013., Results: 170 T1-metformin-exposed pregnancies [119 for diabetes and 51 for polycystic ovary syndrome (PCOS)] were prospectively followed-up and compared with 93 pregnancies of T1-insulin treated women and 530 non-teratogenic exposed (NTE) pregnancies. The differences in the rate of major anomalies excluding genetic/cytogenetic, and spontaneously resolved cardiovascular anomalies were not significant [4.4% (2/45) - metformin-PCOS, 1.1% (1/90) - metformin-diabetes, 2.5% (2/80) - insulin, and 1.7% (9/519) - NTE; OR adj metformin / NTE 1.77; 95% CI 0.45-7.01; OR adj insulin / NTE 1.69; 95% CI 0.35-8.11]. The rate of Cesarean section was higher in both the metformin-diabetes 51/90 (56.7%) and insulin 45/79 (57.0%) groups compared with the NTE group [138/503 (27.4%)]., Conclusion: Metformin-T1-exposure per se is not associated with an increased risk of major anomalies., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Lamotrigine is a second-generation antiepileptic drug, also used as a mood stabilizer. Published data on its use in human pregnancy are largely derived from pregnancy registries. Pregnancy experience in most studies has been reassuring. However, data from the North American Antiepileptic Drug Pregnancy Registry suggested an increased risk for oral clefts. The primary objective of the study was to evaluate the rate of major anomalies after lamotrigine exposure during pregnancy compared with pregnancies of women counseled for nonteratogenic exposure (NTE)., Methods: Callers who contacted the Israeli Teratology Information Service regarding lamotrigine treatment or NTE during pregnancy between 1997 and 2008 were prospectively followed-up., Results: The rate of major congenital anomalies was similar between 218 lamotrigine exposed pregnancies (208 in the first trimester) and 865 NTE-pregnancies. There was no case of oral cleft in the lamotrigine-exposed group. The median lamotrigine dose in the beginning of pregnancy was 200 mg/d. The dose was increased during pregnancy in 29%. The majority of women in the cohort (82%) were treated for neurologic indications, while 18% for psychiatric disorders. Monotherapy was taken by 72%., Conclusion: The data available, thus far, on lamotrigine monotherpy-exposed pregnancies are encouraging. However, further studies are needed to determine with greater certainty the overall risk for major anomalies, as well as the specific risk for oral clefts. Based on the current and previously published data, lamotrigine, seems a reasonable alternative for pregnant women when clinically indicated. Birth Defects Research 109:1196-1203, 2017. © 2017 Wiley Periodicals, Inc., (© 2017 Wiley Periodicals, Inc.)

Introduction: Methylphenidate is a central nervous system stimulant medicinally used in the treatment of attention-deficit disorder with or without hyperactivity (ADD/ADHD). Data on its use in human pregnancy are limited. The primary objective of the study was to evaluate the risk of major congenital anomalies after pregnancy exposure to methylphenidate for medical indications., Methods: In a prospective, comparative, multicenter observational study performed in 4 participating Teratology Information Services (in Jerusalem, Berlin, Newcastle upon Tyne, and Toronto) between 1996 and 2013, methylphenidate-exposed pregnancies were compared with pregnancies counseled for nonteratogenic exposure (NTE) after matching by maternal age, gestational age, and year at initial contact., Results: 382 methylphenidate-exposed pregnancies (89.5% in the first trimester) were followed up. The overall rate of major congenital anomalies was similar between the groups (10/309 = 3.2% [methylphenidate] vs 13/358 = 3.6% [NTE], P = .780). The rates of major congenital anomalies (6/247 = 2.4% [methylphenidate] vs 12/358 = 3.4% [NTE], P = .511) and cardiovascular anomalies (2/247 = 0.8% [methylphenidate] vs 3/358 = 0.8% [NTE], P = .970) were also similar after exclusion of genetic or cytogenetic anomalies and limiting methylphenidate exposure to the period of organogenesis (weeks 4-13 after the last menstrual period). There was a higher rate of miscarriages and elective terminations of pregnancy in the methylphenidate group. Significant predictors for the miscarriages using Cox proportional hazards model were methylphenidate exposure (adjusted hazard ratio [HR] = 1.98; 95% CI, 1.23-3.20; P = .005) and past miscarriage (adjusted HR = 1.35; 95% CI, 1.18-1.55; P < .001)., Conclusions: The present study suggests that methylphenidate does not seem to increase the risk for major malformations. Further studies are required to establish its pregnancy safety and its possible association with miscarriages., (© Copyright 2016 Physicians Postgraduate Press, Inc.)

Background: Dental treatment and use of local anesthetics during pregnancy generally are considered harmless because of lack of evidence of adverse pregnancy effects. Data on the safety of dental treatment and local anesthetics during pregnancy are scant. Dental care is often a reason for concern both among women and their health care providers. The primary objective of this study was to evaluate the rate of major anomalies after exposure to local anesthetics as part of dental care during pregnancy., Methods: The authors performed a prospective, comparative observational study at the Israeli Teratology Information Services between 1999 and 2005., Results: The authors followed 210 pregnancies exposed to dental local anesthetics (112 [53%] in the first trimester) and compared them with 794 pregnancies not exposed to teratogens. The rate of major anomalies was not significantly different between the groups (4.8% versus 3.3%, P = .300). There was no difference in the rate of miscarriages, gestational age at delivery, or birth weight. The most common types of dental treatment were endodontic treatment (43%), tooth extraction (31%), and tooth restoration (21%). Most women (63%) were not exposed to additional medications. Approximately one-half (51%) of the women were not exposed to dental radiography, and 44% were exposed to radiation, mostly bite-wing radiography., Conclusions: This study's results suggest that use of dental local anesthetics, as well as dental treatment during pregnancy, do not represent a major teratogenic risk., Practical Implications: There seems to be no reason to prevent pregnant women from receiving dental treatment and local anesthetics during pregnancy., (Copyright © 2015 American Dental Association. Published by Elsevier Inc. All rights reserved.)

Objective: The authors conducted a prospective, comparative observational study to evaluate the risk of major anomalies following exposure to lithium during pregnancy., Method: A total of 183 lithium-exposed pregnancies of women who contacted the Israeli Teratology Information Service were followed up (90.2% in the first trimester) and compared with 72 disease-matched and 748 nonteratogenic-exposed pregnancies., Results: There were significantly more miscarriages (adjusted odds ratio=1.94, 95% CI=1.08-3.48) and elective terminations of pregnancy (17/183 [9.3%] compared with 15/748 [2.0%]) in the lithium-exposed group compared with the nonteratogenic exposure group. The rate of major congenital anomalies after exclusion of genetic or cytogenetic anomalies was not significantly different between the three groups (lithium-exposed in the first trimester: 8/123 [6.5%]; bipolar: 2/61 [3.3%]; nonteratogenic: 19/711 [2.7%]). Cardiovascular anomalies occurred more frequently in the lithium group exposed during the first trimester when compared with the nonteratogenic exposure group (5/123 [4.1%] compared with 4/711 [0.6%]) but not after excluding anomalies that spontaneously resolved (3/123 [2.4%] compared with 2/711 [0.3%]). Ebstein's anomaly was diagnosed in one lithium-exposed fetus and in two retrospective lithium cases that were not included because contact with the information service was made after the prenatal diagnosis by ultrasound. The rate of noncardiovascular anomalies was not significantly different between the groups. The rate of preterm deliveries was higher in the lithium group compared with the nonteratogenic exposure group (18/131 [13.7%] compared with 41/683 [6.0%])., Conclusions: Lithium treatment in pregnancy is associated with a higher rate of cardiovascular anomalies. Women who are treated with lithium during organogenesis should undergo fetal echocardiography and level-2 ultrasound.

Objective: High-dose methotrexate (MTX) exposure during pregnancy is associated with embryopathy. The teratogenic potential of MTX at dosages typically used in the treatment of rheumatic diseases remains uncertain. The aim of this study was to evaluate the risk of spontaneous abortion, major birth defects, elective termination of pregnancy, shortened gestational age at delivery, and reduced birth weight in women exposed to MTX., Methods: Pregnancy outcome in women taking MTX (≤30 mg/week) either after conception or within the 12 weeks before conception was evaluated in a prospective observational multicenter cohort study. Pregnancy outcomes in the MTX group were compared to outcomes in a group of disease-matched women and a group of women without autoimmune diseases (neither group was exposed to MTX)., Results: The study sample included 324 MTX-exposed pregnancies (188 exposed post-conception, 136 exposed pre-conception), 459 disease-matched comparison women, and 1,107 comparison women without autoimmune diseases. In the post-conception cohort, the cumulative incidence of spontaneous abortion was 42.5% (95% confidence interval [95% CI] 29.2-58.7), which was significantly higher than the incidence of spontaneous abortion in either comparison group. The risk of major birth defects (7 of 106 [6.6%]) was elevated compared to both the cohort of women without autoimmune diseases (29 of 1,001 [2.9%]) (adjusted odds ratio [OR] 3.1 [95% CI 1.03-9.5]) and the disease-matched cohort (14 of 393 [3.6%]) (adjusted OR 1.8 [95% CI 0.6-5.7]). None of the malformations were clearly consistent with MTX embryopathy. Neither the cumulative incidence of spontaneous abortion (14.4% [95% CI 8.0-25.3]) nor the risk of major birth defects (4 of 114 [3.5%]) was increased in the pre-conception cohort. Elective termination rates were increased in both of the MTX-exposed cohorts. There were no other significant differences among groups in other study end points., Conclusion: Post-conception administration of MTX at dosages typically used in the treatment of rheumatic diseases was associated with an increased risk of major birth defects and spontaneous abortion. Such evidence was not found among women in our pre-conception cohort., (Copyright © 2014 by the American College of Rheumatology.)

Objective: To evaluate pregnancy safety of anti-TNF-α medications., Design: Prospective, comparative, observational study done at the Israeli Teratology Information Service between 2002 and 2011., Results: 83 anti-TNF-α-exposed-pregnancies (97.6% in the first trimester, T1) were followed-up and compared with 86 disease-matched (DM) and 341 non-teratogenic-exposed (NTE) pregnancies. The anti-TNF-α group consisted of 35 infliximab-, 25 etanercept-, and 23 adalimumab-exposed pregnancies. The rate of major congenital anomalies did not significantly differ between the three groups [3/65 (4.6%) (anti-TNF-α, T1), 5/79 (6.3%) (DM), 8/336 (2.4%) (NTE)], even after excluding genetic or cytogenetic anomalies [3/65 (4.6%) (anti-TNF-α, T1), 4/79 (5.1%) (DM), 6/336 (1.8%) (NTE)]. There were no cases of VATER/VACTERL association., Conclusion: The present study suggests that anti-TNF-α treatment does not pose a major teratogenic risk in humans. This conclusion is based on relatively small numbers of exposed pregnancies and should be interpreted with caution. Larger studies are needed to establish anti-TNF-α pregnancy safety., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objective: To evaluate pregnancy safety of hydroxychloroquine (HCQ) for rheumatologic diseases., Design: Prospective comparative observational study done at the Israeli teratology information service between 1998 and 2006., Results: 114 HCQ-exposed pregnancies (98.2% in the first trimester, T1) were followed-up and compared with 455 pregnancies of women counseled for non-teratogenic exposure. The difference in the rate of congenital anomalies was not statistically significant [7/97 (7.2%) vs. 15/440 (3.4%), p=0.094]. The analysis was repeated among those exposed in T1 excluding genetic or cytogenetic anomalies or congenital infections [5/95 (5.3%) vs. 14/440 (3.2%), p=0.355]. There were no cases of neonatal lupus erythematosus. The gestational age at delivery was earlier, rate of preterm delivery higher, and birth weight lower, in the HCQ group., Conclusion: The present study suggests that HCQ treatment in pregnancy is not a major human teratogen. The earlier gestational age and lower birth weight might be associated with maternal disease., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objective: To examine first trimester safety of angiotensin-converting-enzyme-inhibitors (ACEIs) or angiotensin-receptor-blockers (ARBs)., Study Design: Prospective observational cohort regarding pregnancy ACEI/ARBs-exposure including contacts to two Teratology Information Services in Israel (1994-2007) and Italy (1990-2008), with two comparison groups: (1) exposed to other antihypertensives (OAH) (2) after non-teratogenic exposure (NTE) in similar time frames., Results: 252 ACEI/ARBs-exposed, 256 OAH-exposed and 495 NTE-exposed pregnancies were followed-up. The rate of major congenital anomalies was comparable between the groups (8/190, 4.2%, ACEI/ARB; 9/212, 4.2%, OAH; 18/471, 3.8% NTE; p = 0.954) among first trimester exposed pregnancies. The median gestational age at delivery was two weeks earlier, rate of preterm deliveries more than 2-fold higher, and median birth weight more than 200 g lower in the ACEI/ARB and OAH groups compared to the NTE group., Conclusion: The present study suggests that ACEI/ARBs are not major teratogens when used in the first trimester, and can reassure women with similar exposures., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Objective: We sought to examine the fetal safety of colchicine., Study Design: This was a prospective observational comparative cohort study regarding colchicine exposure during pregnancy including contacts to 2 Teratology Information Services in Israel from 1994 through 2006., Results: In all, 238 colchicine-exposed pregnancies (97.0% first trimester) and 964 pregnancies with nonteratogenic exposure were followed up. Treatment indications were: familial Mediterranean fever (87.3%), Behçet disease (7.5%), or other (5.2%). The rate of major congenital anomalies was comparable between the groups (10/221 [4.5%] vs 35/908 [3.9%]; P = .648). There were no cytogenetic anomalies in the colchicine group. The median gestational age at delivery was earlier (39 [38-40] vs 40 [38-41] weeks; P < .001), the rate of preterm deliveries was higher (32/214 [15.0%] vs 51/867 [5.9%]; P < .001), and the median birthweight was lower (3000 [2688-3300] vs 3300 [2900-3600] g; P < .001) in the colchicine group., Conclusion: The present study suggests that colchicine does not appear to be a major human teratogen, and, probably, has no cytogenetic effect., (Copyright (c) 2010 Mosby, Inc. All rights reserved.)

Aims: Propylthiouracil (PTU) is presently considered to be the treatment of choice for hyperthyroidism in pregnancy. It is known to cross the human placenta, and therefore may affect the fetus. The major aims of this study were to evaluate the rate of major anomalies and to report the rate of fetal goitre, accompanied by hypothyroidism, in fetuses/ newborns of mothers after in utero exposure to PTU., Methods: Prospective observational controlled cohort study of PTU-exposed pregnancies of women counselled by the Israeli Teratology Information Service between the years 1994 and 2004 compared with women exposed to nonteratogens., Results: We followed up 115 PTU-exposed pregnancies and 1141 controls. The rate of major anomalies was comparable between the groups [PTU 1/80 (1.3%), control 34/1066 (3.2%), P= 0.507]. Hypothyroidism was found in 9.5% of fetuses/neonates (56.8% of whom with goitre). Hyperthyroidism, possibly resulting from maternal disease, was found in 10.3%. Goitres prenatally diagnosed by ultrasound were successfully treated in utero by maternal dose adjustment. In most cases neonatal thyroid functions normalized during the first month of life without any treatment. Median neonatal birth weight was lower [PTU 3145 g (2655-3537) vs. control 3300 g (2968-3600), P= 0.018]., Conclusions: PTU does not seem to be a major human teratogen. However, it could cause fetal/neonatal hypothyroidism with or without goitre. Fetal thyroid size monitoring and neonatal thyroid function tests are important for appropriate prevention and treatment.

Objectives: To determine whether the use of the new macrolides (azithromycin, clarithromycin, roxithromycin) during the first trimester of pregnancy is associated with an increased risk of major malformations., Study Design: In a prospective multi-center study, pregnancy outcome was compared between pregnant women exposed to one of the new macrolides during the first trimester of pregnancy and two comparison groups one exposed to other antibiotics and the other to other non-teratogenic medications. All women enrolled in the study called one of the three participating teratogen information services (TIS). Group 1 macrolides (n=161), group 2 other antibiotics (n=213) and group 3 non-teratogens (n=740)., Results: A total of 161 women exposed to the new macrolides (118 were exposed in the first trimester of pregnancy) and 953 from a comparison groups were followed up. The rate of major malformations in the study group was 4.1% compared to 2.1% in the other antibiotics exposed group (OR=1.41, 95% CI 0.47-4.23) and 3.0% in the non-teratogens exposed group. The rate of elective terminations of pregnancy was significantly higher in the exposed group in compare to both comparison groups., Conclusion: Our study, although relatively small sized, suggests that the use of the new macrolides during the first trimester of pregnancy does not represent an increased risk for congenital malformations strong enough for an induced abortion after such an exposure. Elective terminations of pregnancy because of early exposure to these medications should be reconsidered.

Aims: Recent studies have suggested a possible association between maternal use of selective serotonin reuptake inhibitors (SSRIs) in early pregnancy and cardiovascular anomalies. The aim of the present study was to evaluate the teratogenic risk of paroxetine and fluoxetine., Methods: This multicentre, prospective, controlled study evaluated the rate of major congenital anomalies after first-trimester gestational exposure to paroxetine, fluoxetine or nonteratogens., Results: We followed up 410 paroxetine, 314 fluoxetine first-trimester exposed pregnancies and 1467 controls. After exclusion of genetic and cytogenetic anomalies, there was a higher rate of major anomalies in the SSRI groups compared with the controls [paroxetine 18/348 (5.2%), fluoxetine 12/253 (4.7%) and controls 34/1359 (2.5%)]. The main risk applied to cardiovascular anomalies [paroxetine 7/348 (2.0%), crude odds ratio (OR) 3.47, 95% confidence interval (CI) 1.13, 10.58; fluoxetine 7/253 (2.8%), crude OR, 4.81 95% CI 1.56, 14.71; and controls 8/1359 (0.6%)]. On logistic regression analysis only cigarette smoking of >or=10 cigarettes day(-1) and fluoxetine exposure were significant variables for cardiovascular anomalies. The adjusted ORs for paroxetine and fluoxetine were 2.66 (95% CI 0.80, 8.90) and 4.47 (95% CI 1.31, 15.27), respectively., Conclusion: This study suggests a possible association between cardiovascular anomalies and first-trimester exposure to fluoxetine.

Background: Epstein-Barr virus (EBV) is one of the most common human viruses. To date, there is limited information regarding the influence of maternal EBV infection on pregnancy outcome., Objective: Our aim was to examine the fetal safety of EBV infection in pregnancy., Study Design: We prospectively evaluated the rate of major anomalies and pregnancy outcome of women with serologic evidence of primary, recurrent or undefined infection (27, 56, and 43 women, respectively) compared to 1434 women who called the Israeli TIS for non-teratogenic exposure., Results: Women's characteristics and pregnancy outcome were comparable between the EBV exposed and control groups. Similarly, the gestational age at delivery and birth weight were not significantly different. The rate of major congenital anomalies did not significantly differ between the EBV exposed compared to the control group., Conclusion: This study suggests that EBV infection during pregnancy does not represent a major teratogenic risk to the fetus.

We examined prospectively the outcome of primary and nonprimary maternal cytomegalovirus (CMV) infection during pregnancy among 88 and 120 women, respectively. The risk for vertical transmission was 1.83x higher for primary infection than for nonprimary infection. Nonetheless, congenital CMV disease was diagnosed in both infection groups at similar rates.

Synergistic interactions could prove to be relevant when evaluating the toxicity of environmental pollutants in a complex mixture, especially when organic and inorganic substances co-occur at concentrations currently considered to be low-toxic or sublethal. Escherichia coli cells (SR-9 strain) were used as a model system for studying the cellular toxicity of environmental pollutants. Exposure of bacterial cells to a combination of pentachlorophenol (PCP) and a positively charged complex of iron or copper caused a dramatic inhibition of growth and an increase in cell death. Incubation of bacterial cells with PCP and either ferric-1,10-phenanthroline complex [Fe3+(OP)3]3+ (500 and 5 microM, respectively) or cupric-1,10-phenanthroline complex [Cu2+(OP)2]2+ (400 and 0.05 microM, respectively) showed two and four log units of cell death, respectively, in 30 min. In contrast, only minor amounts of cell death were observed with each component alone. Similar effects have been shown for other positively charged complexes of transition metals and for other biocides. The observed synergism was associated with the formation of novel noncharged and lipophilic ternary complexes, which contain PCP anions (or other polychlorinated anions) and the iron (or copper) complex. The ternary complexes demonstrated effective transport of their components into the cells.

Objective: To assess the safety of the butyrophenone neuroleptics haloperidol and penfluridol in pregnancy., Method: The rate of major anomalies was compared between a cohort of pregnant women counseled for gestational exposure to haloperidol or penfluridol and a control group counseled for nonteratogen exposure. This multicenter, prospective, controlled study was conducted within the European Network of Teratology Information Services (ENTIS) and included women who contacted 1 of 4 teratology information services for counseling between January 1989 and December 2001., Results: We followed up on the outcomes of 215 pregnancies exposed to haloperidol (N = 188) or penfluridol (N = 27)-78.2% (of 206) were in the first trimester-and compared to outcomes of 631 ENTIS controls. The rate of congenital anomalies did not differ between the haloperidol/penfluridol-exposed group and the control group (6/179 = 3.4% vs. 22/581 = 3.8%, p = .787). No difference was found by limiting the analysis to those exposed to butyrophenones during the first trimester. There were 2 cases of limb defects in the butyrophenone-exposed group (1 after haloperidol and 1 after penfluridol exposure) and none in the controls. A higher rate of elective terminations of pregnancy (8.8% vs. 3.8%, p = .004), a higher rate of preterm birth (13.9% vs. 6.9%, p = .006), a lower median birth weight (3155 g vs. 3370 g, p < .001), and a lower median birth weight of full-term infants (3250 g vs. 3415 g, p = .004) were found in the butyrophenone-exposed group compared to the controls., Conclusion: This study suggests that haloperidol and penfluridol do not represent a major teratogenic risk. Since a possible association between butyrophenone exposure and limb defects cannot be ruled out with this sample size, a level II ultrasound with emphasis on the limbs should be considered in pregnancies with first trimester exposure.

Aims: The number of published studies on the use of amoxycillin/clavulanic acid during pregnancy is small and so is the number of pregnancies investigated in those studies. In this study we wished to investigate prospectively the safety of intrauterine exposure to amoxycillin/clavulanic acid in a relatively large cohort of women., Methods: Women treated (n = 191) with amoxycillin/clavulanic acid during the first trimester of pregnancy were recruited from two teratogen information centres in Israel. Exposed women were matched for age, smoking habits and alcohol consumption with 191 controls exposed to amoxycillin only for similar medical indications., Results: Maternal age, birth weight, gestational age at delivery, rates of live births and abortions were comparable between the two groups. Rates of major malformations in the amoxycillin/clavulanic acid group (3/158, 1.9%) did not differ significantly from controls (5/163, 3%) (P = 0.49, relative risk = 0.62, 95% confidence interval 0.15, 2.55), and were within the expected baseline risk for the general population., Conclusion: These data suggest that exposure to amoxycillin/clavulanic acid during pregnancy is unlikely to be associated with an increased risk of malformations.

Objective: To evaluate the safety of glucocorticosteroids (GCS) in pregnancy., Study Design: The Israeli Teratogen Information Service (TIS) prospectively collected and followed 311 pregnancies counseled regarding systemic use of different GCS in the first trimester. The rate of major congenital anomalies was compared to that of 790 controls who were counseled for non-teratogenic exposure., Results: The rate of major anomalies did not significantly differ between the groups [12/262 = 4.6% (GCS), 19/728 = 2.6% (control), [P = 0.116 ]. There was no case of oral cleft and no pattern of anomalies among the GCS exposed group. Higher rates of miscarriages (11.5% versus 7.0%, P = 0.013) and preterm births (22.7% versus 10.8%, P < 0.001 ) were observed among the GCS exposed group compared to the controls. GCS exposed infants had a lower median birth weight [3080 g versus 3290 g, P < 0.001 ] and were born at an earlier median gestational age [39 weeks versus 40, P < 0.001 ] compared to the control., Conclusions: The present study supports that GCS do not represent a major teratogenic risk in humans. The study was powered to find a 2.5-fold increase in the overall rate of major anomalies.

Background: Loratadine is a second-generation histamine H(1)-receptor antagonist, used in the treatment of allergic conditions. No prospective controlled trials on loratadine in human pregnancy have been published to date., Objective: To determine whether the use of loratadine or other antihistamines (OAH) is associated with an increased risk of major anomalies., Methods: Callers who were counseled by the Israeli Teratogen Information Service in regard to loratadine or OAH exposure during pregnancy were prospectively collected and followed up. Pregnancy outcome was compared among three exposure groups: loratadine, OAH, and a control group of patients who were counseled for nonteratogenic exposure, nonteratogenic controls (NTC). The OAH included astemizole, chlorpheniramine, terfenadine, hydroxyzine, promethazine, and dimetindene., Results: We followed up 210 pregnancies exposed to loratadine (77.9% in the first trimester) and 267 pregnancies exposed to OAH (64.6% in the first trimester) and compared pregnancy outcome with that of 929 NTC. The rate of congenital anomalies did not differ among the groups [loratadine: 4/175 (2.3%), OAH: 10/247 (4.0%), NTC: 25/844 (3.0%), P =.553, relative risk (RR), 0.77; 95% confidence interval (CI), 0.27 to 2.19, (loratadine vs NTC); RR, 0.56; 95% CI, 0.18 to 1.77, (loratadine vs OAH)]. The rate did not differ between those exposed to antihistamines in the first trimester and the control patients [loratadine: 1/126 (0.8%), OAH: 7/146 (4.8%), NTC: 25/844 (3.0%), P =.152, RR, 0.27; 95% CI, 0.04 to 1.94, (loratadine vs NTC); RR, 0.17; 95% CI, 0.02 to 1.33, (loratadine vs OAH)]., Conclusions: This study on the use of loratadine in human pregnancy suggests that this agent does not represent a major teratogenic risk. The study was powered to find a 3-fold increase in the overall rate of major anomalies.

Objective: Mebendazole is an anthelmintic that is commonly needed in women of reproductive age. Its use in pregnancy is a reason for concern for women and their health care providers. The purpose of this study was to examine the fetal safety of mebendazole., Study Design: The Israeli Teratogen Information Service prospectively collected and followed 192 pregnancies exposed to mebendazole in pregnancy, 71.5% of whom had first-trimester exposure. Pregnancy outcome was compared with that of a matched control group, who were counseled for nonteratogenic exposure., Results: There was no increase in the rate of major malformations between the groups (5/150 pregnancies [3.3%; mebendazole] vs 3/175 pregnancies [1.7%; nonteratogenic control subjects]; P =.478). There was a higher rate of elective terminations of pregnancy in the exposed group compared with the control group (22/192 pregnancies [11.5%; mebendazole] vs 3/192 pregnancies [1.6% [nonteratogenic control subjects]; P =.000)., Conclusion: This study suggests that mebendazole does not represent a major teratogenic risk in humans when it is used in the doses that are used commonly for pinworm (Enterobius vermicularis) infestation.

The role of the antioxidant defense mechanism in diabetes-induced anomalies was studied in the Cohen diabetes-sensitive (CDs) and -resistant (CDr) rats, a genetic model of nutritionally induced type 2 diabetes mellitus. Embryos, 12.5-day-old, of CDs and CDr rats fed regular diet (RD) or a diabetogenic high-sucrose diet (HSD) were monitored for growth retardation and congenital anomalies. Activity of superoxide dismutase (SOD) and catalase-like enzymes and levels of ascorbic acid (AA), uric acid (UA), and dehydroascorbic acid (DHAA) were measured in embryonic homogenates. When fed RD, CDs rats had a decreased rate of pregnancy, and an increased embryonic resorption. CDs embryos were smaller than CDr embryos; 46% were maldeveloped and 7% exhibited neural tube defects (NTDs). When fed HSD, rate of pregnancy was reduced, resorption rate was greatly increased (56%; P < .001), 47.6% of the embryos were retrieved without heart beats, and 27% exhibited NTD. In contrast, all the CDr embryos were normal when fed RD or HSD. Activity of SOD and catalase was not different in embryos of CDs and CDr rats fed RD. When fed HSD, levels of AA were significantly reduced, the ratio DHAA/AA was significantly increased, and SOD activity was not sufficiently increased when compared to embryos of CDr. The reduced fertility of the CDs rats, the growth retardation, and NTD seem to be genetically determined. Maternal hyperglycemia seems to result in environmentally induced embryonic oxidative stress, resulting in further embryonic damage.

Both pentachlorophenol (PCP) and copper compounds have been widely used as wood preservatives, and are commonly found not only in the area near wood-preserving facilities, but also in body fluids and tissues of people who are not occupationally exposed to them. In this study, we found that exposing bacteria to a combination of PCP and copper at non- or sub-toxic concentrations resulted in enhanced cytotoxic effect in a synergistic mode as indicated by both the inhibition of growth and the lowering of the colony-forming ability. The toxicity of the combination PCP/Cu(II) was relieved by hydrophilic chelating agents, thiol compounds and adventitious proteins, but was markedly potentiated by low levels of the lipophilic metal chelating agents.