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Varenicline is a smoking cessation aid for which limited data exist concerning safety during human pregnancy. This multicentre prospective observational comparative cohort study was undertaken using surveillance data collected by the European Network of Teratology Information Services. The study sample consisted of 89 varenicline exposed pregnancies and two matched comparator groups; 267 non-teratogen exposed (NTE) controls and 78 exposed to nicotine replacement therapy or bupropion (NRT/B) for smoking cessation. For all exposed pregnancies, varenicline use only occurred in the first trimester, with a considerable proportion discontinuing use in the very early stages of pregnancy. The major congenital malformation rate (n=2/89, 2.25%) was in keeping with the expected background rate (2-4%), and was not significantly increased for first trimester varenicline-exposed infants in comparison with non-exposed controls (vs. NTE: OR 2.02, 95%CI 0.166 to 17.9, vs. NRT/B: OR 0.874, 95%CI 0.0620 to 12.3). However, the small sample size produced very imprecise risk estimates.

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BACKGROUND: Proton pump inhibitors are used to treat gastro-oesophageal reflux and peptic ulcers. Gastro-oesophageal reflux is a common condition in pregnancy. Human pregnancy experience with lansoprazole or pantoprazole is very limited. More data exist on the safety of omeprazole in pregnancy. AIM: To assess the safety of proton pump inhibitors in pregnancy. METHODS: The rate of major anomalies was compared between pregnant women exposed to omeprazole, lanzoprazole, or pantoprazole and a control group counselled for non-teratogens. The study design is a multicentre (n = 8), prospective, controlled study of the European Network of Teratology Information Services. RESULTS: We followed up 295 pregnancies exposed to omeprazole [233 in the first trimester (T1)], 62 to lansoprazole (55 in T1) and 53 to pantoprazole (47 in T1), and compared pregnancy outcome to that of 868 European Network of Teratology Information Services controls. The rate of major congenital anomalies did not differ between the exposed and control groups [omeprazole nine of 249 (3.6%), lansoprazole two of 51 (3.9%) and pantoprazole one of 48 (2.1%) vs. controls 30 of 792 = 3.8%]. No differences were found when exposure was limited to the first trimester after exclusion of genetic, cytogenetic or infectious anomalies. CONCLUSIONS: This study suggests that proton pump inhibitors do not represent a major teratogenic risk in humans.

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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.

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BACKGROUND: Metronidazole is an important antibacterial agent commonly used in women of reproductive age. Its use in pregnancy is a reason for concern for women and their health care providers. The objective was to examine the fetal safety of metronidazole. METHODS: The Israeli Teratogen Information Service prospectively collected and followed up 228 women exposed to metronidazole in pregnancy, 86.2% of whom with first-trimester exposure. Pregnancy outcome was compared with that of a control group, who were counseled during the same period for nonteratogenic exposure. RESULTS: There was no difference in the rate of major malformations between the groups (3/190; 1.6% [metronidazole] vs. 8/575; 1.4% [control], P = 0.739). The rate of major malformations did not differ between the groups even after including elective terminations of pregnancy due to prenatally diagnosed malformations (5/192; 2.6% [metronidazole] vs. 12/579; 2.1% [control], P = 0.777). A reduced neonatal birth weight was found in the metronidazole group compared with controls without significant differences in the rate of prematurity or in gestational age at delivery. The mean birth weight was lower in the metronidazole group when comparing the subgroup of term infants. CONCLUSIONS: This study confirms that metronidazole does not represent a major teratogenic risk in humans when used in the recommended doses.

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BACKGROUND: Corticosteroids are first-line drugs for the treatment of a variety of conditions in women of childbearing age. Information regarding human pregnancy outcome with corticosteroids is limited. METHODS: We collected prospectively and followed up 184 women exposed to prednisone in pregnancy and 188 pregnant women who were counseled by Motherisk for nonteratogenic exposure. The primary outcome was the rate of major birth defects. A meta-analysis of all epidemiological studies was conducted. The Mantel-Haenszel summary odds ratio was calculated for the pooled studies with 95% confidence intervals. A cumulative summary odds ratio was also calculated by combining studies in chronological order. Chi-squared for homogeneity was determined to establish the comparability of the studies. RESULTS: In our prospective study, there was no statistical difference in the rate of major anomalies between the corticosteroid-exposed and control groups. In the meta-analysis, the Mantel-Haenszel summary odds ratio for major malformations with all cohort studies was 1.45 [95% CI 0.80, 2.60] and 3.03 [95% CI 1.08, 8. 54] when Heinonen et al. ('77) was removed. This suggests a marginally increased risk of major malformations after first-trimester exposure to corticosteroids. In addition, summary odds ratio for case-control studies examining oral clefts was significant (3.35 [95% CI 1.97, 5.69]). CONCLUSIONS: Although prednisone does not represent a major teratogenic risk in humans at therapeutic doses, it does increase by an order of 3.4-fold the risk of oral cleft, which is consistent with the existing animal studies.

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QUESTION: One of my patients, whom I had treated with a 2-week course of zopiclone for insomnia, conceived while using the medication. She is concerned. How should I advise her? ANSWER: Based on available, albeit limited, evidence, zopiclone does not appear to be a major human teratogen.

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BACKGROUND & AIM: Zopiclone, a cyclopyrrolone derivative, is a short-acting hypnotic. To date, no published data exist regarding human pregnancy experience with zopiclone. The purpose of this study was to compare pregnancy outcome following first-trimester exposure to zopiclone with that of a matched control group of women, who were counseled for nonteratogenic exposure. METHODS: The Motherisk Program, the Toronto Teratogen Information Service, prospectively collected and followed up 40 women exposed to zopiclone during pregnancy. Pregnancy outcome was compared with that of a matched control group of women, who were counseled for nonteratogenic exposure. RESULTS: There was no increase in the rate of major malformations (0 of 31 [0%] for zopiclone vs. 1 of 37 [2.7%] for nonteratogenic controls; p = 1). CONCLUSIONS: Our study, which is the first cohort on zopiclone use during embryogenesis, albeit small, suggests that zopiclone does not appear to be a major human teratogen. Larger studies are needed to establish its safety during pregnancy.

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Data suggest a large variability in the effectiveness of the orally active iron chelator, deferiprone, in inducing a sustained decrease in body iron to concentrations compatible with the avoidance of complications from iron overload. We analyzed 19 patients with thalassemia major who were undergoing long-term therapy with deferiprone (75 mg/kg/day every 8 hours). In seven of the 19 patients, hepatic iron concentration had been reduced or maintained at less than 7 mg/g of dry weight liver tissue, associated with no evidence of iron-induced toxicity (group A). In the remaining 12, hepatic iron concentration had either stabilized at higher than 7 mg/g of dry weight liver tissue, or increased to such concentrations during therapy with deferiprone (group B). We studied in these patients determinants that may explain such variability, including initial hepatic iron concentrations, compliance, transfusion index, pharmacokinetic characteristics of deferiprone, and plasma vitamin C status. Patients in group B showed significantly decreased plasma vitamin C concentrations compared with those in group A, who demonstrated normal levels (0.04 mg/dl [0.04-0.19 mg/dl] and 0.62 mg/day [0.44-1.05 mg/day], respectively; p = 0.02). A significant difference in apparent volume of distribution (Vd/F) had developed between the groups over time, with a higher Vd/F in group B (1.66 [0.681, group A] and 3.16 [0.811, group B]; p = 0.006). Group B had started with hepatic iron concentrations that were significantly higher than those of group A, a difference that became more pronounced over time. In the initial analysis, serum ferritin concentrations were also higher in group B. The two groups did not differ in the remaining factors. The initial hepatic iron concentrations predicted the slope of change in this value. Regression analysis suggested that patients with initial hepatic iron concentration of less than or equal to 7.22 mg/g of dry weight liver tissue are unlikely to further decrease while taking deferiprone 75 mg/kg/day. Vitamin C deficiency developed in patients in group B over time. Vitamin C is an important biologic cofactor that plays a role in the distribution of iron. The trend of increase in Vd/F of deferiprone over time may imply a compartment shift of iron stores to one less accessed by deferiprone. This study confirmed the effectiveness of deferiprone in heavily iron-loaded patients and provided evidence that its effectiveness decreases in proportion to liver iron load.

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A patient being treated for sickle cell disease with hydroxyurea (1 g/d) conceived, and drug treatment was discontinued at nine weeks gestational age. The pregnancy and delivery were complicated by vaso-occlusive crises. A healthy male infant was born at 39 weeks with no evidence of congenital malformations. A literature review, including this case, suggests that the risk of hydroxyurea exposure during in pregnancy may have been overestimated. Further studies are required to determine its safety in pregnancy.

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BACKGROUND & AIMS: Mesalamine is a first-line drug in the treatment of inflammatory bowel disease. Information regarding human pregnancy experience with mesalamine has been scarce and uncontrolled despite its frequent use in women of childbearing age. The aim of this study was to examine the fetal safety of mesalamine. METHODS: The Motherisk Program prospectively enrolled and followed up 165 women exposed to mesalamine during pregnancy, 146 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 major malformations (1 of 127 [0.8%] for mesalamine vs. 5 of 131 [3.8%] for nonteratogenic controls; P = 0.23). There was an increase in the rate of preterm deliveries (13.0% for mesalamine vs. 4.7% for nonteratogenic controls; P = 0.02), a decrease in the mean maternal weight gain during pregnancy (13.1 +/- 6.3 kg for mesalamine vs. 15.6 +/- 6.0 kg for nonteratogenic controls; P = 0.0002), and a decrease in the mean birth weight (3253 +/- 546 g for mesalamine vs. 3461 +/- 542 g for nonteratogenic controls; P = 0.0005). There were no significant differences in the maternal obstetric history, rates of live births, miscarriages, pregnancy terminations, ectopic pregnancies, delivery method, or fetal distress between the groups. CONCLUSIONS: This study suggests that mesalamine does not represent a major teratogenic risk in humans when used in the recommended doses.

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Deferiprone is the most widely studied oral iron chelator and, at present, the only one shown to be effective in achieving negative iron balance in long-term clinical trials for chronic iron overload. Because of its adverse effects (e.g., agranulocytosis and arthropathy) its use is presently restricted to clinical trials and to countries where desferrioxamine is unavailable. Deferiprone was licensed for clinical use in India in 1995. Clinical trials are in progress in many centers worldwide that will provide further information on the long-term effectiveness of deferiprone as well as on the incidence of serious adverse effects in patients with iron overload. Trials of combined use of deferiprone and desferrioxamine are also in progress. In the meantime, deferiprone is an acceptable alternative for patients who cannot use desferrioxamine because of serious adverse effects, lack of compliance, or unavailability. Elucidation of the mechanisms involved in the agranulocytosis and arthropathy associated with deferiprone is still needed, as are methods to predict individual susceptibility to these adverse effects and ways of preventing them. In addition, new indications for iron-chelating therapy are continuously being explored.

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The most serious adverse effect of deferiprone, the first orally active iron chelator, is agranulocytosis afflicting an estimated 1.6% of patients. Among the 13 reported patients who had experienced deferiprone-induced agranulocytosis or severe neutropenia, 5 were rechallenged. We studied the onset, clinical and rechallenge course of all 5 patients in an attempt to characterise the mechanisms involved in deferiprone-induced agranulocytosis, to verify whether rechallenge in future patients is ethically justified. Deferiprone-induced agranulocytosis showed no trend of dose dependency: of all patients who had experienced agranulocytosis 23% were treated with 50 mg/kg/day, 46% with 75 to 90 mg/kg/day, and 31 % with > 90 mg/kg/day. Available data including bone marrow aspiration in some patients support the hypothesis that an early myeloid precursor is the target cell affected by deferiprone. All 5 rechallenged patients re-experienced agranulocytosis/neutropenia. The lag period to agranulocytosis/neutropenia following reinduction was significantly shorter (13.2 ± 21.7 weeks compared with 46.4 ± 14.2 weeks in the first episode; p < 0.05). All but one of the rechallenged patients re-experienced agranulocytosis or neutropenia 2 to 4 weeks following re-exposure to deferiprone, suggesting a possible immune mechanism. We found that deferiprone was oxidised in vitro by hypochlorous acid, the major neutrophil oxidant to produce a myelotoxic metabolite. This reactive species demonstrated neutrophil toxicity and a dose-dependent lymphotoxic curve. However, we found no differences in the toxicity of this reactive species to neutrophils from 2 patients with a history of deferiprone-induced agranulocytosis when compared with controls. In combination with the clinical characteristics, these results suggest a reactive metabolite-induced immune-mediated reaction. These 5 rechallenged cases ethically preclude the rechallenge of additional cases.