Svetlana Shechtman

Is carbamazepine teratogenic? A prospective controlled study of 210 pregnancies

The Israeli Teratogen Information Service prospectively followed up 210 pregnancies with first trimester carbamazepine exposure. Pregnancy outcome was compared with that of two overlapping controls, matched and general (n = 629), exposed to nonteratogenic agents. Our study suggests a twofold increase in the rate of major congenital anomalies (12/160 [carbamazepine] versus 18/560 [general control]; relative risk 2.24; 95% CI 1.1–4.56) and a birth weight reduction of approximately 250 g after in utero exposure to carbamazepine.

Is benzodiazepine use during pregnancy really teratogenic

Benzodiazepines (BDs) have a widespread use among people suffering from anxiety. These drugs easily cross the placenta and may affect the developing embryo and fetus. The literature is divided as to whether BD may cause an increase in spontaneous abortions or congenital anomalies. From the years 1988 to 1996, 756 women called the Israeli TIS concerning exposures to BD prior to or during pregnancy. Of 599 women who called us during pregnancy, we have follow-up information on 460 pregnancies (76.6%). The incidence of congenital anomalies (3.1%) was not different from that found in 424 control pregnancies (2.6%). There was a significantly higher incidence of induced abortions (14.1% vs. 4.7%, P = 0.00) and of spontaneous abortions (8.7% vs. 5.2%, P = 0.01). From an examination of our results, it does not appear that BD during pregnancy caused an increase in the incidence of birth defects. There was no specific defect in the offspring. The increase in the rate of induced abortions is probably related to the counseling of the callers, and the increase in spontaneous abortions seems to be a result of the lower gestational age at the time of counseling in the women exposed to BD. It is unknown whether BD could be responsible for developmental or behavioral problems, which are observed only at a later stage.

Pregnancy outcome following in utero exposure to lithium: a prospective, comparative, observational study.

OBJECTIVEnThe authors conducted a prospective, comparative observational study to evaluate the risk of major anomalies following exposure to lithium during pregnancy.nnnMETHODnA 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.nnnRESULTSnThere 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%]). Ebsteins 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%]).nnnCONCLUSIONSnLithium 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.

Pregnancy outcome after in utero exposure to valproate : evidence of dose relationship in teratogenic effect.

AbstractBackground: 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.n 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.n 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 ≥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.n 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.

The outcome of pregnancy following topiramate treatment: A study on 52 pregnancies

In spite of a substantial increase in the use of topiramate at child bearing age, very little is known regarding its use in pregnancy. We describe the outcome of 52 pregnancies with 41 liveborn infants from which it seems that topiramate reduces birth weight without decreasing gestational age at delivery, but does not seem to increase the risk for structural defects. There was an increased rate of spontaneous abortions not related to the drug effects.

The role of reactive oxygen species in diabetes-induced anomalies in embryos of Cohen diabetic rats.

The role of the antioxidant defense mechanism in diabetesinduced 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 catalaselike 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 fedRD. 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.

Primary versus Nonprimary Cytomegalovirus Infection during Pregnancy, Israel

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 1.83× higher for primary infection than for nonprimary infection. Nonetheless, congenital CMV disease was diagnosed in both infection groups at similar rates.

Pregnancy outcome after gestational exposure to the new macrolides: a prospective multi-center observational study.

OBJECTIVESnTo 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.nnnSTUDY DESIGNnIn 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).nnnRESULTSnA 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.nnnCONCLUSIONnOur 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.

Synergistic cytotoxicity between pentachlorophenol and copper in a bacterial model

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.

Methylphenidate in Pregnancy: A Multicenter, Prospective, Comparative, Observational Study

INTRODUCTIONnMethylphenidate 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.nnnMETHODSnIn 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.nnnRESULTSn382 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).nnnCONCLUSIONSnThe 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.