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Evaluation of the cardiovascular function during gestation in Sprague–Dawley rats continuously infused with physiological saline
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Posters / Reproductive Toxicology 30 (2010) 233–248
Methods: In a prospective follow-up study we collected data of pregnancy outcomes after medication with paroxetine (n = 222) between 1990 and 2009. Our Teratology Information Service (TIS) was contacted by physicians and patients after exposure to paroxetine in the first trimester. We compared the results with a control group (n = 733) of our TIS in the same interval, which was not or not severely exposed. Statistical evaluation was performed by Fisher’s Exact Test and Mann–Whitney Test. Results: Both samples did not differ in gestational age at first contact (median: paroxetine group 50 days vs control group 51 days). After exposure to paroxetine 20 patients (20/222 = 9.0%) preferred a termination of pregnancy. The incidence of elective terminations of pregnancy was much higher (p < 0.001) after medication with paroxetine than in the control group (19/733 = 2.6%). The other 202 documented pregnancies ended with spontaneous abortion in 23 cases and live births in 179 cases. The abortion rate (23/202 = 11.4%) did not differ significantly from the control group (81/714 = 11.3%). Four congenital anomalies were reported after intrauterine exposure to paroxetine: clubfeet after exposure throughout pregnancy (40 mg/d), large naevus flammeus after maternal medication up to week 7 (100 mg/d), spastic torticollis after medication up to week 12 (20 mg/d), unilateral renal agenesia (10 mg/d, long term medication). The rate of congenital anomalies was not increased after application of paroxetine in early pregnancy (4/179 = 2.2% vs 25/633 = 3.9%; relative risk 0.56; 95% confidence interval 0.17, 1.67). Conclusions: Our prospective controlled follow-up study does not support the assumption of a teratogenic effect of paroxetine. doi:10.1016/j.reprotox.2010.05.074 Evaluation of the cardiovascular function during gestation in Sprague–Dawley rats continuously infused with physiological saline Louise Pouliot ∗ , Nathalie Hébert, Stephanie Barbeau, Annie Martin, Keith Robinson Charles River Laboratories, Preclinical Services, Montréal, Québec, Canada The cardiovascular and reproductive functions of female Sprague–Dawley (CD-IGS) rats were evaluated during gestation (gestation Days [GD] 0–21) and during continuous intravenous infusion of physiological saline (0.9% sodium chloride injection, USP) at a rate of 2 mL/kg/h, via an indwelling catheter. Surgical implantation of a silastic cannula into a femoral vein and of a transmitter (DSI TA11PA-C40) subcutaneously in the flank was performed in 10-week old female Sprague–Dawley rats, under aseptic conditions. Patency of the cannula was maintained by continuous infusion of physiological saline at a rate of 0.4 mL/h. Following a 1-week recovery period, continuous monitoring of cardiovascular parameters (heart rate, mean arterial pressure, systolic and diastolic blood pressure and pulse pressure) was initiated using the Life Science Suite software (TM PO-NE-MAH Physiology Platform P3 software-DSI Open ART). Two days later, the instrumented females were placed for mating with proven breeder males. The intravenous infusion-rate of physiological saline (0.9% sodium chloride injection, USP) in mated females was increased to 2 mL/kg/h between GD 6 and 17. The oestrous cycles, the pre- and post-mating clinical condition, body weights and food intake of the dams were evaluated. Caesarean-section and gross pathological examinations were performed on GD 21 and the foetuses were weighed, sexed and examined for external, visceral and skeletal abnormalities. The presence of the implanted catheter and transmitter was well tolerated by the dams. There was no evidence of adverse effects on
the reproductive function and embryo-foetal development secondary to the experimental procedures. Continuous monitoring of the cardiovascular parameters revealed apparent decreases in systolic, diastolic, mean and pulse pressures during the later part of gestation, with no related effects on the heart rate. It was concluded that effects upon cardiovascular function of pregnant rats can be monitored during continuous infusion of pharmaceutical and biotechnology products. doi:10.1016/j.reprotox.2010.05.075 Interaction of protein, zinc and carbon monoxide on skeletal malformations in mice Jarnail Singh Stillman College, Tuscaloosa, AL, USA Introduction: Deficiencies of protein, zinc, and chronic malnutrition are widespread in the diets of poor pregnant women throughout the world. Carbon monoxide (CO) pollution is rising at an alarming rate in many developing countries, making it a serious public health problem in developing as well as developed countries. The effect of interaction of these factors on skeletal malformation is not known. Methods: A three way (3 × 3 × 3) factorial experiment was used. Pregnant dams of CD-1 mice were placed on diets of 9% (deficient), 17% (control), or 25% (supplemental) protein on gestation day (GD) 1. Protein diets were mixed with deficient, normal (control), or supplemental zinc. The dams were exposed to air (control), 250 or 500 ppm CO in air in environmental chambers from GD 8–18. A total of 228 dams were used for the study. There were 8.4 litters in each treatment of protein/zinc/CO combination. Daily food intake per dam in each protein/zinc/CO treatment was presented at the ETS meeting of 2008 [1]. On GD 18 dams were sacrificed, fetuses removed, and processed by double staining for skeletal examination of malformations Results: Malformations of skull, mouth, ribs, limbs, and tail were lowest in the control protein (17%) and normal zinc groups. Deficient protein and zinc, and supplemental protein and zinc increased the incidence of these malformations. In a three way interaction, skull malformations ranged from 30.9% in the 25% protein/normal zinc/500 ppm CO to 100% in the 17% protein/zinc deficient/500 ppm CO. Mouth malformations ranged from 0% in the 17% protein/normal zinc/0 ppm CO to 100% in the 25% protein/deficient zinc/250 ppm CO. The incidence of cervical centra malformations was high (close to 100%) in many treatments. These treatments included all proteins/zinc deficient/all CO exposed groups. Rib malformations ranged from 0% in the 25% protein/supplemental zinc/0 ppm CO to 100% in the 9% protein/supplemental zinc/500 ppm CO. Sternebra malformations ranged from 15.4% in the 17% protein/supplemental zinc/0 ppm CO to 100% in the 9% protein/zinc deficient/250 ppm CO. Limb malformations ranged from 0% in the 25% protein/zinc supplement/0 ppm CO to 100% in the 25% protein/zinc deficient/250 ppm CO. Tail malformations ranged from 0% in the17% protein/supplemental zinc/0 ppm CO to 100% in the 25% protein/zinc deficient/500 ppm CO. Conclusion: The data indicate that 3 levels of protein along with zinc deficiencies, and CO pollution interact to increase the incidence of skeletal malformations. This interaction seems to be complex, and may explain the reason for high rate of malformations in human populations in developing countries. The results of the study may be relevant to human populations that experience protein and or zinc deficiencies during gestation and are exposed CO pollution, or cigarette, or marijuana smoke during pregnancy. Supported by NIGMS Grant Number S06GM063709.
Posters / Reproductive Toxicology 30 (2010) 233–248
Methods: In a prospective follow-up study we collected data of pregnancy outcomes after medication with paroxetine (n = 222) between 1990 and 2009. Our Teratology Information Service (TIS) was contacted by physicians and patients after exposure to paroxetine in the first trimester. We compared the results with a control group (n = 733) of our TIS in the same interval, which was not or not severely exposed. Statistical evaluation was performed by Fisher’s Exact Test and Mann–Whitney Test. Results: Both samples did not differ in gestational age at first contact (median: paroxetine group 50 days vs control group 51 days). After exposure to paroxetine 20 patients (20/222 = 9.0%) preferred a termination of pregnancy. The incidence of elective terminations of pregnancy was much higher (p < 0.001) after medication with paroxetine than in the control group (19/733 = 2.6%). The other 202 documented pregnancies ended with spontaneous abortion in 23 cases and live births in 179 cases. The abortion rate (23/202 = 11.4%) did not differ significantly from the control group (81/714 = 11.3%). Four congenital anomalies were reported after intrauterine exposure to paroxetine: clubfeet after exposure throughout pregnancy (40 mg/d), large naevus flammeus after maternal medication up to week 7 (100 mg/d), spastic torticollis after medication up to week 12 (20 mg/d), unilateral renal agenesia (10 mg/d, long term medication). The rate of congenital anomalies was not increased after application of paroxetine in early pregnancy (4/179 = 2.2% vs 25/633 = 3.9%; relative risk 0.56; 95% confidence interval 0.17, 1.67). Conclusions: Our prospective controlled follow-up study does not support the assumption of a teratogenic effect of paroxetine. doi:10.1016/j.reprotox.2010.05.074 Evaluation of the cardiovascular function during gestation in Sprague–Dawley rats continuously infused with physiological saline Louise Pouliot ∗ , Nathalie Hébert, Stephanie Barbeau, Annie Martin, Keith Robinson Charles River Laboratories, Preclinical Services, Montréal, Québec, Canada The cardiovascular and reproductive functions of female Sprague–Dawley (CD-IGS) rats were evaluated during gestation (gestation Days [GD] 0–21) and during continuous intravenous infusion of physiological saline (0.9% sodium chloride injection, USP) at a rate of 2 mL/kg/h, via an indwelling catheter. Surgical implantation of a silastic cannula into a femoral vein and of a transmitter (DSI TA11PA-C40) subcutaneously in the flank was performed in 10-week old female Sprague–Dawley rats, under aseptic conditions. Patency of the cannula was maintained by continuous infusion of physiological saline at a rate of 0.4 mL/h. Following a 1-week recovery period, continuous monitoring of cardiovascular parameters (heart rate, mean arterial pressure, systolic and diastolic blood pressure and pulse pressure) was initiated using the Life Science Suite software (TM PO-NE-MAH Physiology Platform P3 software-DSI Open ART). Two days later, the instrumented females were placed for mating with proven breeder males. The intravenous infusion-rate of physiological saline (0.9% sodium chloride injection, USP) in mated females was increased to 2 mL/kg/h between GD 6 and 17. The oestrous cycles, the pre- and post-mating clinical condition, body weights and food intake of the dams were evaluated. Caesarean-section and gross pathological examinations were performed on GD 21 and the foetuses were weighed, sexed and examined for external, visceral and skeletal abnormalities. The presence of the implanted catheter and transmitter was well tolerated by the dams. There was no evidence of adverse effects on
the reproductive function and embryo-foetal development secondary to the experimental procedures. Continuous monitoring of the cardiovascular parameters revealed apparent decreases in systolic, diastolic, mean and pulse pressures during the later part of gestation, with no related effects on the heart rate. It was concluded that effects upon cardiovascular function of pregnant rats can be monitored during continuous infusion of pharmaceutical and biotechnology products. doi:10.1016/j.reprotox.2010.05.075 Interaction of protein, zinc and carbon monoxide on skeletal malformations in mice Jarnail Singh Stillman College, Tuscaloosa, AL, USA Introduction: Deficiencies of protein, zinc, and chronic malnutrition are widespread in the diets of poor pregnant women throughout the world. Carbon monoxide (CO) pollution is rising at an alarming rate in many developing countries, making it a serious public health problem in developing as well as developed countries. The effect of interaction of these factors on skeletal malformation is not known. Methods: A three way (3 × 3 × 3) factorial experiment was used. Pregnant dams of CD-1 mice were placed on diets of 9% (deficient), 17% (control), or 25% (supplemental) protein on gestation day (GD) 1. Protein diets were mixed with deficient, normal (control), or supplemental zinc. The dams were exposed to air (control), 250 or 500 ppm CO in air in environmental chambers from GD 8–18. A total of 228 dams were used for the study. There were 8.4 litters in each treatment of protein/zinc/CO combination. Daily food intake per dam in each protein/zinc/CO treatment was presented at the ETS meeting of 2008 [1]. On GD 18 dams were sacrificed, fetuses removed, and processed by double staining for skeletal examination of malformations Results: Malformations of skull, mouth, ribs, limbs, and tail were lowest in the control protein (17%) and normal zinc groups. Deficient protein and zinc, and supplemental protein and zinc increased the incidence of these malformations. In a three way interaction, skull malformations ranged from 30.9% in the 25% protein/normal zinc/500 ppm CO to 100% in the 17% protein/zinc deficient/500 ppm CO. Mouth malformations ranged from 0% in the 17% protein/normal zinc/0 ppm CO to 100% in the 25% protein/deficient zinc/250 ppm CO. The incidence of cervical centra malformations was high (close to 100%) in many treatments. These treatments included all proteins/zinc deficient/all CO exposed groups. Rib malformations ranged from 0% in the 25% protein/supplemental zinc/0 ppm CO to 100% in the 9% protein/supplemental zinc/500 ppm CO. Sternebra malformations ranged from 15.4% in the 17% protein/supplemental zinc/0 ppm CO to 100% in the 9% protein/zinc deficient/250 ppm CO. Limb malformations ranged from 0% in the 25% protein/zinc supplement/0 ppm CO to 100% in the 25% protein/zinc deficient/250 ppm CO. Tail malformations ranged from 0% in the17% protein/supplemental zinc/0 ppm CO to 100% in the 25% protein/zinc deficient/500 ppm CO. Conclusion: The data indicate that 3 levels of protein along with zinc deficiencies, and CO pollution interact to increase the incidence of skeletal malformations. This interaction seems to be complex, and may explain the reason for high rate of malformations in human populations in developing countries. The results of the study may be relevant to human populations that experience protein and or zinc deficiencies during gestation and are exposed CO pollution, or cigarette, or marijuana smoke during pregnancy. Supported by NIGMS Grant Number S06GM063709.