- Email: [email protected]
Case report – CNS malformation after first and second trimester exposure to phenprocoumon
220
Abstracts / Reproductive Toxicology 57 (2015) 210–227
condition characterized by acute brain injury arising from perinatal hypoxia. In our case fetal tachycardia, that could be a symptom of SS, resolved soon after partum while muscular hypertonia with increased CK levels and hyperthermia above 38.5 ◦ C non responsive to antipyretics, a characteristic clinical picture of SS, were ensued 4 hours after delivery. To the best of our knowledge, SSRI treatment has never been related to HIE as well as HIE has never been associated with SS, even though the serotoninergic network in the brain could be disrupted in a rodent model of preterm hypoxia-ischemia. Therefore, in the present case, SS and HIE were two distinct overlapping conditions: when SS symptoms (masking those of HIE) disappeared, the dramatic consequences of antenatal hypoxia became evident. Since the disturbance in the balance between dopaminergic and serotonergic systems leads to or may worsen SS, it is possible that the concomitant in utero exposure to perphenazine (acting on dopaminergic receptors) and sertraline (acting on serotoninergic system) led a more vulnerable (because of HIE) fetus to develop a serotonin syndrome of such severity. http://dx.doi.org/10.1016/j.reprotox.2015.06.025 Case report – CNS malformation after first and second trimester exposure to phenprocoumon Cornelia Borisch, Corinna Weber-Schoendorfer, Christof Schaefer Pharmakovigilanzzentrum Embryonaltoxikologie, Charité Universitätsmedizin Berlin, (Berlin Institute for Clinical Teratology and Drug Risk Assessment in Pregnancy), Germany Introduction: Phenprocoumon is a coumarin derivative which is used as an oral anticoagulant for prevention of thromboembolic events in patients with, for example, atrial fibrillation, venous thromboembolism or with a prosthetic heart valve. Use of phenprocoumon and other vitamin K antagonists (VKA) during pregnancy increases the risk of structural malformations and adverse pregnancy outcome. It can lead to a characteristic pattern of malformations in prenatally exposed children. The embryopathy occurs rarely and mainly consists of midface hypoplasia, anomalies of the skeleton including stippled epiphysis, growth retardation, and CNS anomalies. Some genetic syndromes such as chondrodysplasia punctata show a similar phenotype. Method: Retrospectively ascertained case report. Results: We describe a 34-year-old G4P0 (BMI 36.1; cigarette smoker (20 cig/d); no use of alcohol or illicit drugs) whose geneticist contacted our Teratology Information Service because the patient had taken phenprocoumon (Marcumar® ) until gestational week 24 + 4 days when she recognised her pregnancy. Additionally, she took sertraline due to an anxiety disorder and levothyroxine because of Hashimoto-thyroiditis. Phenprocoumon was given for recurrent leg- and arm-vein-thrombosis and a related Factor-V-mutation which was diagnosed a few years ago. After recognition of pregnancy phenprocoumon was replaced by enoxaparin. A detailed prenatal ultrasound showed a Dandy-Walker malformation, a hypoplastic vermis cerebelli, and a corpuscallosum-agenesis. Because of the poor prognosis feticide was performed. Post-mortem examination confirmed the prenatal diagnosis and additionally, showed craniofacial dysmorphism (slight hypertelorism, flat nose with broad bridge, shallow philtrum, and retrognathia). No other malformations were identified. Chromosome analysis was normal (46, XX) and cytogenetic and molecular genetic diagnostic tests did not reveal a distinct pathogenic mutation. Interestingly, in her third pregnancy the fetus was diagnosed with hydrocephalus and aplasia of cerebellum after the mother had taken phenprocoumon until gestational week 6.
Conclusion: Our case report describing a Dandy-Walkermalformation in association with VKA and a preceding pregnancy affected with fetal CNS defects highlights the difficulties of unambiguous assignment of malformations to a distinct cause even in cases of established teratogens. http://dx.doi.org/10.1016/j.reprotox.2015.06.026 Acute intoxication during pregnancy: The experience of Florence teratology information service and poison control centre Isabella Orsini 1 , Alessandra Ieri 2 , Francesco Gambassi 2 , Andrea Missanelli 3 , Brunella Occupati 3 , Valentina Galli 3 , Carlo Smorlesi 3 , Guido Mannaioni 1,3 , Emanuela Masini 1,3 , Alessandra Pistelli 3 1
Department of Neuroscience, Psychology, Drug Research and Child Health, Università degli Studi di Firenze, Firenze, Italy 2 Poison Control Centre, Italy 3 SOD Tossicologia Medica e Centro di Riferimento Regionale Tossicologia Perinatale, Azienda Ospedaliero-Universitaria Careggi, Firenze, Italy Introduction: Acute intoxication during pregnancy may be accidental or intentional and could be responsible for adverse pregnancy and foetal outcome. Methods: We retrospectively analyzed available data on pregnant women admitted to the Toxicology Unit of Florence University Hospital due to acute intoxication between 1995 and 2014. Results: Fifty different hospital admissions regarding 45 pregnant women were studied. Fifteen women attempted suicide with drug overdose and 2 via bleach ingestion while 33 presented an accidental poisoning due to carbon monoxide exposure (15), mushroom ingestion (4), and ethanol (12) or drug-of- abuse (2) overdose. Medical records were available for 29 admissions (27 patients): 9 intoxications occurred during the first trimester, 14 during the second and 6 during the third one. On admission one patient was unconscious due to benzodiazepines overdose whereas 28 patients did not show any clinical sign (4 of them had had a previous loss of consciousness). Obstetric ultrasound was performed in 20 patients, showing 19 live fetuses and a poorly vital one. Psychoactive drugs, analgesics, hormones were abused in voluntary intoxication. Interestingly, among accidental carbon monoxide exposure observed during pregnancy, 14 women out of 16 were exposed to brazier fumes and all coming from foreign countries. Mushroom poisoning was reported as due to short-term incubation syndrome in 3 cases and to long-term incubation in 1 case. Fourteen healthy babies (1 twin birth) were born. One elective (ETOP), 2 therapeutic termination of pregnancy in psychiatric patients and 3 miscarriages were reported. One pregnancy is still ongoing. Spontaneous abortion occurred during carbon monoxide intoxication at week 8: 1 case, with maternal COHb level equaling 22% and showing poor fetal vitality on ER admission, and 2 following opioid and ethanol overdose at week 8 and 12, respectively. Eight women were lost to follow up. Conclusions: Our experience confirms that acute intoxication during pregnancy is a rare event in an emergency department. However, considering the peculiarity of pregnancy per se and the need of a quick maternal and foetal medical management, a multidisciplinary professional approach is requested in this utmost delicate clinical challenge. http://dx.doi.org/10.1016/j.reprotox.2015.06.027
Abstracts / Reproductive Toxicology 57 (2015) 210–227
condition characterized by acute brain injury arising from perinatal hypoxia. In our case fetal tachycardia, that could be a symptom of SS, resolved soon after partum while muscular hypertonia with increased CK levels and hyperthermia above 38.5 ◦ C non responsive to antipyretics, a characteristic clinical picture of SS, were ensued 4 hours after delivery. To the best of our knowledge, SSRI treatment has never been related to HIE as well as HIE has never been associated with SS, even though the serotoninergic network in the brain could be disrupted in a rodent model of preterm hypoxia-ischemia. Therefore, in the present case, SS and HIE were two distinct overlapping conditions: when SS symptoms (masking those of HIE) disappeared, the dramatic consequences of antenatal hypoxia became evident. Since the disturbance in the balance between dopaminergic and serotonergic systems leads to or may worsen SS, it is possible that the concomitant in utero exposure to perphenazine (acting on dopaminergic receptors) and sertraline (acting on serotoninergic system) led a more vulnerable (because of HIE) fetus to develop a serotonin syndrome of such severity. http://dx.doi.org/10.1016/j.reprotox.2015.06.025 Case report – CNS malformation after first and second trimester exposure to phenprocoumon Cornelia Borisch, Corinna Weber-Schoendorfer, Christof Schaefer Pharmakovigilanzzentrum Embryonaltoxikologie, Charité Universitätsmedizin Berlin, (Berlin Institute for Clinical Teratology and Drug Risk Assessment in Pregnancy), Germany Introduction: Phenprocoumon is a coumarin derivative which is used as an oral anticoagulant for prevention of thromboembolic events in patients with, for example, atrial fibrillation, venous thromboembolism or with a prosthetic heart valve. Use of phenprocoumon and other vitamin K antagonists (VKA) during pregnancy increases the risk of structural malformations and adverse pregnancy outcome. It can lead to a characteristic pattern of malformations in prenatally exposed children. The embryopathy occurs rarely and mainly consists of midface hypoplasia, anomalies of the skeleton including stippled epiphysis, growth retardation, and CNS anomalies. Some genetic syndromes such as chondrodysplasia punctata show a similar phenotype. Method: Retrospectively ascertained case report. Results: We describe a 34-year-old G4P0 (BMI 36.1; cigarette smoker (20 cig/d); no use of alcohol or illicit drugs) whose geneticist contacted our Teratology Information Service because the patient had taken phenprocoumon (Marcumar® ) until gestational week 24 + 4 days when she recognised her pregnancy. Additionally, she took sertraline due to an anxiety disorder and levothyroxine because of Hashimoto-thyroiditis. Phenprocoumon was given for recurrent leg- and arm-vein-thrombosis and a related Factor-V-mutation which was diagnosed a few years ago. After recognition of pregnancy phenprocoumon was replaced by enoxaparin. A detailed prenatal ultrasound showed a Dandy-Walker malformation, a hypoplastic vermis cerebelli, and a corpuscallosum-agenesis. Because of the poor prognosis feticide was performed. Post-mortem examination confirmed the prenatal diagnosis and additionally, showed craniofacial dysmorphism (slight hypertelorism, flat nose with broad bridge, shallow philtrum, and retrognathia). No other malformations were identified. Chromosome analysis was normal (46, XX) and cytogenetic and molecular genetic diagnostic tests did not reveal a distinct pathogenic mutation. Interestingly, in her third pregnancy the fetus was diagnosed with hydrocephalus and aplasia of cerebellum after the mother had taken phenprocoumon until gestational week 6.
Conclusion: Our case report describing a Dandy-Walkermalformation in association with VKA and a preceding pregnancy affected with fetal CNS defects highlights the difficulties of unambiguous assignment of malformations to a distinct cause even in cases of established teratogens. http://dx.doi.org/10.1016/j.reprotox.2015.06.026 Acute intoxication during pregnancy: The experience of Florence teratology information service and poison control centre Isabella Orsini 1 , Alessandra Ieri 2 , Francesco Gambassi 2 , Andrea Missanelli 3 , Brunella Occupati 3 , Valentina Galli 3 , Carlo Smorlesi 3 , Guido Mannaioni 1,3 , Emanuela Masini 1,3 , Alessandra Pistelli 3 1
Department of Neuroscience, Psychology, Drug Research and Child Health, Università degli Studi di Firenze, Firenze, Italy 2 Poison Control Centre, Italy 3 SOD Tossicologia Medica e Centro di Riferimento Regionale Tossicologia Perinatale, Azienda Ospedaliero-Universitaria Careggi, Firenze, Italy Introduction: Acute intoxication during pregnancy may be accidental or intentional and could be responsible for adverse pregnancy and foetal outcome. Methods: We retrospectively analyzed available data on pregnant women admitted to the Toxicology Unit of Florence University Hospital due to acute intoxication between 1995 and 2014. Results: Fifty different hospital admissions regarding 45 pregnant women were studied. Fifteen women attempted suicide with drug overdose and 2 via bleach ingestion while 33 presented an accidental poisoning due to carbon monoxide exposure (15), mushroom ingestion (4), and ethanol (12) or drug-of- abuse (2) overdose. Medical records were available for 29 admissions (27 patients): 9 intoxications occurred during the first trimester, 14 during the second and 6 during the third one. On admission one patient was unconscious due to benzodiazepines overdose whereas 28 patients did not show any clinical sign (4 of them had had a previous loss of consciousness). Obstetric ultrasound was performed in 20 patients, showing 19 live fetuses and a poorly vital one. Psychoactive drugs, analgesics, hormones were abused in voluntary intoxication. Interestingly, among accidental carbon monoxide exposure observed during pregnancy, 14 women out of 16 were exposed to brazier fumes and all coming from foreign countries. Mushroom poisoning was reported as due to short-term incubation syndrome in 3 cases and to long-term incubation in 1 case. Fourteen healthy babies (1 twin birth) were born. One elective (ETOP), 2 therapeutic termination of pregnancy in psychiatric patients and 3 miscarriages were reported. One pregnancy is still ongoing. Spontaneous abortion occurred during carbon monoxide intoxication at week 8: 1 case, with maternal COHb level equaling 22% and showing poor fetal vitality on ER admission, and 2 following opioid and ethanol overdose at week 8 and 12, respectively. Eight women were lost to follow up. Conclusions: Our experience confirms that acute intoxication during pregnancy is a rare event in an emergency department. However, considering the peculiarity of pregnancy per se and the need of a quick maternal and foetal medical management, a multidisciplinary professional approach is requested in this utmost delicate clinical challenge. http://dx.doi.org/10.1016/j.reprotox.2015.06.027