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Acute voluntary intoxication with selective serotonin reuptake inhibitors during the third trimester of pregnancy: therapeutic management of mother and fetus
Case Report
www. AJOG.org
Acute voluntary intoxication with selective serotonin reuptake inhibitors during the third trimester of pregnancy: therapeutic management of mother and fetus Hervé Tixier, MD; Cecile Feyeux, MS; Sophie Girod, MD; Ségoléne Thouvenot, MD; Mathieu Morisse, MD; Serge Douvier, PhD; Paul Sagot, PhD
E
scitalopram is a selective serotonin reuptake inhibitor (SSRI) antidepressant. Acute voluntary intoxication with SSRI is characterized by a variety of clinical manifestations, which can be digestive (nausea, vomiting), neurological (confusion, trembling, fasciculations, somnolence, insomnia, agitation, convulsions), sometimes restless leg syndrome, and hyponatremia. At very high doses, serotoninergic syndrome and sometimes signs of anticholinergic syndrome may be found. Classical management of such intoxications is based on decontamination of the digestive system using activated carbon and gastric lavage preferably within 1 hour of ingestion. Symptomatic treatment is then implemented according to the clinical picture. However, to date, no study has reported acute intoxication in a woman in the third trimester of pregnancy. We present here the case of a patient in the 31st week of amenorrhea who had taken a full box of escitalopram, a dose of 280 mg. The consequences for the mother and fetus, as well as the therapeutic management, are described.
From the Department of Gynecology and Obstetrics, University of Dijon School of Medicine, Bocage Teaching Hospital, 2, bd Maréchal de Lattre Tassigny, BP 77908, FR21079 Dijon Cedex, France. Received April 11, 2008; revised June 1, 2008; accepted July 8, 2008. Reprints: Dr Hervé Tixier, Service de Gynécologie-Obstétrique, Médecine Fœtale et Stérilité Conjugale, BP 77908, 21079 Dijon Cedex, France. [email protected]. 0002-9378/free © 2008 Mosby, Inc. All rights reserved. doi: 10.1016/j.ajog.2008.07.024
Selective serotonin reuptake inhibitor (SSRI) antidepressants are preferred to tricyclics, because, for the same efficacy, they are better tolerated. The mechanisms of action are well understood. These drugs may be used during pregnancy. We present here the case of a voluntary intoxication with SSRI in the third trimester of pregnancy. Key words: pregnancy, selective serotonin reuptake inhibitor, voluntary intoxication
C LINICAL C ASE Mrs X, a 36-year-old patient, fifth pregnancy, primipara, was referred to the maternity department after admission to the emergency unit. She was in the 31st week of amenorrhea and had taken an overdose of escitalopram. Her history was marked by a first pregnancy in 2004 with normal full-term delivery followed by 3 miscarriages in the early stages of pregnancy. The present pregnancy was spontaneous and had been followed up regularly. All of the usual examinations had been performed. The triple screen test was normal and ultrasound (US) scans in the first and second trimester showed satisfactory development and revealed no morphological abnormalities. Mrs X had already experienced an episode of depression for which she was hospitalized in 1995. At the time of the second-trimester US scan, she presented psychiatric symptoms associated with a depressive mood (sadness, pessimism, dissatisfaction), a lack of self-esteem, insomnia, and rejection of the pregnancy, suggesting that the depressive syndrome may have been a reaction to discovering the sex of the infant. Because of these symptoms, Mrs X was referred to a psychiatrist on Feb. 20, 2008. During this consultation, treatment with an SSRI antidepressant (escitalopram 10 mg) and a benzodiazepine anxiolytic (alprazolam 0.5 mg) was implemented. On March 7, 2008, at 11:00 AM, she voluntarily swallowed a full box of escitalo-
pram. The emergency services were called to the family home by the husband and arrived at 12:00 noon. He informed the emergency services of the ingestion of a complete box of escitalopram, which was found empty near her, whereas the box was full in the morning. The Table presents the medical parameters for the mother and fetus collected during the hours following the overdose. When the emergency team arrived at the patient’s home, the patient was sleepy, with a Glasgow score estimated at 10/15. There were no hemodynamic or respiratory abnormalities and the electrocardiogram was normal. She was transferred to the Accident and Emergency unit. The patient did not take any other drugs and had not drunk alcohol. At 1:15 PM, her blood was screened for various toxic substances: meprobamate, tricyclic, barbituric, and benzodiazepine antidepressants. All of the tests proved negative. The patient did not present an acute renal failure. The patient was hyperhydrated with 0.9% physiologic saline. She was transferred to the maternity ward at around 3:00 PM, 4 hours after ingestion of the escitalopram. On arrival at the maternity ward at 3:30 PM, the patient was stable, with a Glasgow score of 12/15. She presented serotoninergic signs of acute intoxication with SSRI: somnolence, mental confusion, lack of motor coordination, and
NOVEMBER 2008 American Journal of Obstetrics & Gynecology
e9
Case Report
www.AJOG.org
TABLE
Medical parameters for the mother and fetus collected during the hours following the overdose
ABP
Plus 1 h, emergency department
Plus 2 h 30 min, emergency department
Plus 4 h 30 min, maternity
Plus 10 h 30 min, maternity
Plus 21 h maternity
108/74
108/69
100/60
110/70
110/80
................................................................................................................................................................................................................................................................................................................................................................................
Pulse
84
80
85
80
75
Glasgow Scale
10/15
10/15
12/15
12/15
15/15
................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................
FHR
—
—
Slight variability Baseline at 140 bpm
Slight variability Baseline at 140 bpm
Slight variability Baseline at 140 bpm
Regular (3 min), intense (80–100 bpm)
Infrequent, low intensity
No uterine contractions
Intermediate, short dehiscent external os
Centered, Short 2 fingers EO
................................................................................................................................................................................................................................................................................................................................................................................
Uterine contractions
—
—
................................................................................................................................................................................................................................................................................................................................................................................
State of the cervix
—
—
................................................................................................................................................................................................................................................................................................................................................................................
ABP, ambulatory blood pressure; EO, external orifice of the uterus; FHR, fetal heart rate. Tixier. Voluntary intoxication with SSRI and pregnancy. Am J Obstet Gynecol 2008.
anticholinergic signs: nervous disorders with muttered speech, bilateral mydriasis, and a dry mouth. The fetal heart rate (FHR) showed a baseline of 140 beats per minute (bpm) with variations of less than 5 bpm. Tocography revealed regular intense uterine contractions at 80-100 mm Hg (Figure). Vaginal touch revealed a modified, short, soft, centered cervix, with an external orifice of the uterus (os) of 2 fingers, cephalic mobile presentation. Pelvic US scan performed on arrival revealed a eutrophic fetus with an estimated weight of 1700 g, cephalic presentation, an amniotic fluid index of 120 mm, and an umbilical resistance index of 0.55. In the endovaginal US scan, the cervix measured 38 mm. The patient was given 50 g activated charcoal-carbomix (Laboratory Omega Pharma France, Chatillon, France) 5 hours after the intoxication, at 4:00 PM. Moreover, given the risk of premature delivery, the following examinations were performed: full blood count (FBC) C-reactive protein (CRP), urine cytology and bacteriology, and cervical swab. A calcium-channel blocker tocolytic (nicardipine) at a dose of 50 mL/hour was given intravenously. An intramuscular injection of corticosteroid (12 mg celestene chronodose; betamethasone; laboratory Schering-Plough France, Lee10
vallois Perret, France) was also given to prevent hyaline-membrane disease. For the following 4 hours, the contractions progressively diminished, there was no modification in the cervix, and the FHR remained stable with slight variability on a baseline of 140 bpm. The patient was closely monitored during the following 18 hours in the delivery room and then in the pathologic pregnancy department. The tocolytic was stopped at the 24th hour. The patient was transferred to the psychiatry department after 3 days of surveillance. The obstetrical and maternal follow-up was then normal. The patient was confined naturally at 37 weeks 4 days of amenorrhea. The first 24 hours after the birth were marked by an extreme agitation of the child, who was hospitalized in neonatology. The child did not present respiratory distress, renal failure, vomiting, or convulsions. Gradually this agitation disappeared, but the child persistently showed a constant irritability and a great nervousness. These symptoms had completely disappeared after 17 days, authorizing the return of the child to its residence with his mother, in whom her mental health condition was stabilized.
C OMMENT Serotonin or 5-hydroxy-tryptamine (5HT) is 1 of the principal neurotransmit-
American Journal of Obstetrics & Gynecology NOVEMBER 2008
ters of the central nervous system. It acts by binding to specific receptors in the membranes of target cells. It acts directly on the muscle of the uterus via 5-HT2a receptors and has an indirect central action via 5-HT1-like receptors on intracranial vessels. SSRIs act by increasing serotoninergic neurotransmission by selectively inhibiting the transporter responsible for serotonin reuptake. This leads to an increase in the release of serotonin in the synaptic cleft. SSRIs are better tolerated than tricyclic antidepressants, because of their low affinity for noradrenalin or dopamine transporters and even for muscarinic cholinergic receptors. SSRIs also have no significant clinical effects on hemodynamics or cardiac electrophysiology. At very high doses, SSRIs may trigger serotoninergic syndrome and even signs of anticholinergic syndrome. Serotoninergic syndrome1 is characterized by the simultaneous presence of at least 3 of the following signs: confusion, agitation, delirium, hallucinations, mania, coma, convulsions, myoclonia (the most specific sign), hyperreflexes, sweating, shivering, trembling, diarrhea, fever, or lack of motor coordination. The principal symptoms of anticholinergic syndrome are nervous disorders (agitation, delirium, slight trem-
Case Report
www.AJOG.org
FIGURE
FHR and tocography on arrival in the maternity ward
Tixier. Voluntary intoxication with SSRI and pregnancy. Am J Obstet Gynecol 2008.
bling in the extremities), mydriasis, dryness of the mucous membranes, urinary retention, constipation, and sinusal tachycardia. Apart from the classical clinical signs of acute intoxication with an SSRI, this patient presented the risk of premature delivery, which was a direct consequence of the SSRI overdose. The intense uterine contractions were the direct consequence of the accumulation of serotonin in the synaptic cleft because of the SSRI intoxication. Since the work of Minosyan et al,2 we know that the increase in the answer to serotonin in the rat at the end of the pregnancy is related to an increase in the number of specific 5HT2a receptors rather than to an increase in their sensitivity. Calcium-channel blocker tocolytics act peripherally by blocking the voltagedependent calcium channels in the smooth muscle fibers of the uterus. In the present case, the treatment was
quickly effective. In the case of overdose in the third trimester of pregnancy, it is therefore useful to implement immediate preventive tocolysis to reduce the strength of uterine contractions. Tocometry must be maintained during the first 12-24 hours following ingestion. Even if there are doubts about the quantity ingested, tocolysis must be started, especially because the levels of the SSRI are not measured routinely. The transplacental transfer of escitalopram has been studied in isolated human placentae.3 In comparison with fluoxetine, desmethylcitalopram, an active citalopram metabolite, had significantly slower placental transfer. But in the case of overdose of citalopram, the placental barrier is probably insufficient, and a fetal repercussion is possible. This explains the variability in the FHR. These anomalies in the FHR, unless they become more serious (onset of variable, late, or prolonged slowing; or
tachycardia), must not lead to an emergency cesarean because, in the case of premature birth, management of the newly born infant will be complicated by the onset of severe withdrawal symptoms. Moreover, therapy to prevent hyaline membrane disease must be implemented immediately, especially as the risk of neonatal respiratory distress induced by an SSRI is particularly high,4-6 and there is a risk of persistent pulmonary hypertension.7 The mother and fetus must be monitored closely for the first 24-48 hours. The use of SSRI antidepressants during pregnancy is possible and, if doses are respected, does not seem to trigger neonatal complications,8-10 but the indications must be followed rigorously, and the patient must be followed up closely. However, in the literature, adverse effects in neonates exposed prenatally to escitalopram have been described,11-13 including respiratory distress, irritabil-
NOVEMBER 2008 American Journal of Obstetrics & Gynecology
e11
Case Report ity, vomiting, and convulsions. Typically these symptoms are mild and disappear by 2 weeks of age. Finally, any expectant mother under treatment with an SSRI must have regular gynecological examinations, because cases of serotoninergic syndrome have already been described for normal doses of the drug.14
C ONCLUSION In case of an overdose of an SSRI in the third trimester of pregnancy, tocolysis must be performed systematically. FHR abnormalities because of fetal intoxication must be accepted as long as they remain slight, because neonatal withdrawal symptoms could be difficult to manage. The mother and fetus must be monitored closely during the first 24-48 hours. Expectant mothers under treatment with an SSRI must have regular gynecological examinations. f ACKNOWLEDGMENT We thank Philip Bastable for help in revising the manuscript.
e12
www.AJOG.org REFERENCES 1. Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005;352:1112-20. 2. Minosyan TY, Lu R, Eghbali M, Toro L, Stefani E. Increased 5-HT contractile response in late pregnant rat myometrium is associated with a higher density of 5-HT2A receptors. J Physiol 2007;581:91-7. 3. Heikkine T, Ekblad U, Laine K. Transplacental transfer of citalopram, fluoxetine and their primary demethylated metabolites in isolated perfused human placenta. BJOG 2002; 109:1003-8. 4. Hendrick V, Smith LM, Suri R, Hwang S, Haynes D, Altshuler L. Birth outcomes after prenatal exposure to antidepressant medication. Am J Obstet Gynecol 2003;188:812-5. 5. Nordeng H, Spigset O. Treatment with selective serotonin reuptake inhibitors in the third trimester of pregnancy: effects on the infant. Drug Saf 2005;28:565-81. 6. Oberlander TF, Warburton W, Misri S, Aghajanian J, Hertzman C. Neonatal outcomes after prenatal exposure to selective serotonin reuptake inhibitor antidepressants and maternal depression using population-based linked health data. Arch Gen Psychiatry 2006;63: 898-906. 7. Chambers CD, Hernandez-Diaz S, Van Marter LJ, et al. Selective serotonin-reuptake inhibitors and risk of persistent pulmonary hypertension of the newborn. N Engl J Med 2006; 354:579-87.
American Journal of Obstetrics & Gynecology NOVEMBER 2008
8. Malm H, Klaukka T, Neuvonen PJ. Risks associated with selective serotonin reuptake inhibitors in pregnancy. Obstet Gynecol 2005; 106:1289-96. 9. Way CM. Safety of newer antidepressants in pregnancy. Pharmacotherapy 2007;27: 546-52. 10. Alwan S, Reefhuis J, Rasmussen SA, Olney RS, Friedman JM. Use of selective serotoninreuptake inhibitors in pregnancy and the risk of birth defects. N Engl J Med 2007;356: 2684-92. 11. Laine K, Heikkinen T, Ekblad U, Kero P. Effects of exposure to selective serotonin reuptake inhibitors during pregnancy on serotonergic symptoms in newborns and cord blood monoamine and prolactin concentrations. Arch Gen Psychiatry 2003;60:720-6. 12. Moses-Kolko EL, Bogen D, Perel J, et al. Neonatal signs after late in utero exposure to serotonin reuptake inhibitors: literature review and implications for clinical applications. JAMA 2005;293:2372-83. 13. Sivojelezova A, Shuhaiber S, Sarkissian L, Einarson A, Koren G. Citalopram use in pregnancy: prospective comparative evaluation of pregnancy and fetal outcome. Am J Obstet Gynecol 2005;193:2004-9. 14. Paruchuri P, Godkar D, Anandacoomarswamy D, Sheth K, Niranjan S. Rare case of serotonin syndrome with therapeutic doses of paroxetine. Am J Ther 2006;13:550-2.
www. AJOG.org
Acute voluntary intoxication with selective serotonin reuptake inhibitors during the third trimester of pregnancy: therapeutic management of mother and fetus Hervé Tixier, MD; Cecile Feyeux, MS; Sophie Girod, MD; Ségoléne Thouvenot, MD; Mathieu Morisse, MD; Serge Douvier, PhD; Paul Sagot, PhD
E
scitalopram is a selective serotonin reuptake inhibitor (SSRI) antidepressant. Acute voluntary intoxication with SSRI is characterized by a variety of clinical manifestations, which can be digestive (nausea, vomiting), neurological (confusion, trembling, fasciculations, somnolence, insomnia, agitation, convulsions), sometimes restless leg syndrome, and hyponatremia. At very high doses, serotoninergic syndrome and sometimes signs of anticholinergic syndrome may be found. Classical management of such intoxications is based on decontamination of the digestive system using activated carbon and gastric lavage preferably within 1 hour of ingestion. Symptomatic treatment is then implemented according to the clinical picture. However, to date, no study has reported acute intoxication in a woman in the third trimester of pregnancy. We present here the case of a patient in the 31st week of amenorrhea who had taken a full box of escitalopram, a dose of 280 mg. The consequences for the mother and fetus, as well as the therapeutic management, are described.
From the Department of Gynecology and Obstetrics, University of Dijon School of Medicine, Bocage Teaching Hospital, 2, bd Maréchal de Lattre Tassigny, BP 77908, FR21079 Dijon Cedex, France. Received April 11, 2008; revised June 1, 2008; accepted July 8, 2008. Reprints: Dr Hervé Tixier, Service de Gynécologie-Obstétrique, Médecine Fœtale et Stérilité Conjugale, BP 77908, 21079 Dijon Cedex, France. [email protected]. 0002-9378/free © 2008 Mosby, Inc. All rights reserved. doi: 10.1016/j.ajog.2008.07.024
Selective serotonin reuptake inhibitor (SSRI) antidepressants are preferred to tricyclics, because, for the same efficacy, they are better tolerated. The mechanisms of action are well understood. These drugs may be used during pregnancy. We present here the case of a voluntary intoxication with SSRI in the third trimester of pregnancy. Key words: pregnancy, selective serotonin reuptake inhibitor, voluntary intoxication
C LINICAL C ASE Mrs X, a 36-year-old patient, fifth pregnancy, primipara, was referred to the maternity department after admission to the emergency unit. She was in the 31st week of amenorrhea and had taken an overdose of escitalopram. Her history was marked by a first pregnancy in 2004 with normal full-term delivery followed by 3 miscarriages in the early stages of pregnancy. The present pregnancy was spontaneous and had been followed up regularly. All of the usual examinations had been performed. The triple screen test was normal and ultrasound (US) scans in the first and second trimester showed satisfactory development and revealed no morphological abnormalities. Mrs X had already experienced an episode of depression for which she was hospitalized in 1995. At the time of the second-trimester US scan, she presented psychiatric symptoms associated with a depressive mood (sadness, pessimism, dissatisfaction), a lack of self-esteem, insomnia, and rejection of the pregnancy, suggesting that the depressive syndrome may have been a reaction to discovering the sex of the infant. Because of these symptoms, Mrs X was referred to a psychiatrist on Feb. 20, 2008. During this consultation, treatment with an SSRI antidepressant (escitalopram 10 mg) and a benzodiazepine anxiolytic (alprazolam 0.5 mg) was implemented. On March 7, 2008, at 11:00 AM, she voluntarily swallowed a full box of escitalo-
pram. The emergency services were called to the family home by the husband and arrived at 12:00 noon. He informed the emergency services of the ingestion of a complete box of escitalopram, which was found empty near her, whereas the box was full in the morning. The Table presents the medical parameters for the mother and fetus collected during the hours following the overdose. When the emergency team arrived at the patient’s home, the patient was sleepy, with a Glasgow score estimated at 10/15. There were no hemodynamic or respiratory abnormalities and the electrocardiogram was normal. She was transferred to the Accident and Emergency unit. The patient did not take any other drugs and had not drunk alcohol. At 1:15 PM, her blood was screened for various toxic substances: meprobamate, tricyclic, barbituric, and benzodiazepine antidepressants. All of the tests proved negative. The patient did not present an acute renal failure. The patient was hyperhydrated with 0.9% physiologic saline. She was transferred to the maternity ward at around 3:00 PM, 4 hours after ingestion of the escitalopram. On arrival at the maternity ward at 3:30 PM, the patient was stable, with a Glasgow score of 12/15. She presented serotoninergic signs of acute intoxication with SSRI: somnolence, mental confusion, lack of motor coordination, and
NOVEMBER 2008 American Journal of Obstetrics & Gynecology
e9
Case Report
www.AJOG.org
TABLE
Medical parameters for the mother and fetus collected during the hours following the overdose
ABP
Plus 1 h, emergency department
Plus 2 h 30 min, emergency department
Plus 4 h 30 min, maternity
Plus 10 h 30 min, maternity
Plus 21 h maternity
108/74
108/69
100/60
110/70
110/80
................................................................................................................................................................................................................................................................................................................................................................................
Pulse
84
80
85
80
75
Glasgow Scale
10/15
10/15
12/15
12/15
15/15
................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................
FHR
—
—
Slight variability Baseline at 140 bpm
Slight variability Baseline at 140 bpm
Slight variability Baseline at 140 bpm
Regular (3 min), intense (80–100 bpm)
Infrequent, low intensity
No uterine contractions
Intermediate, short dehiscent external os
Centered, Short 2 fingers EO
................................................................................................................................................................................................................................................................................................................................................................................
Uterine contractions
—
—
................................................................................................................................................................................................................................................................................................................................................................................
State of the cervix
—
—
................................................................................................................................................................................................................................................................................................................................................................................
ABP, ambulatory blood pressure; EO, external orifice of the uterus; FHR, fetal heart rate. Tixier. Voluntary intoxication with SSRI and pregnancy. Am J Obstet Gynecol 2008.
anticholinergic signs: nervous disorders with muttered speech, bilateral mydriasis, and a dry mouth. The fetal heart rate (FHR) showed a baseline of 140 beats per minute (bpm) with variations of less than 5 bpm. Tocography revealed regular intense uterine contractions at 80-100 mm Hg (Figure). Vaginal touch revealed a modified, short, soft, centered cervix, with an external orifice of the uterus (os) of 2 fingers, cephalic mobile presentation. Pelvic US scan performed on arrival revealed a eutrophic fetus with an estimated weight of 1700 g, cephalic presentation, an amniotic fluid index of 120 mm, and an umbilical resistance index of 0.55. In the endovaginal US scan, the cervix measured 38 mm. The patient was given 50 g activated charcoal-carbomix (Laboratory Omega Pharma France, Chatillon, France) 5 hours after the intoxication, at 4:00 PM. Moreover, given the risk of premature delivery, the following examinations were performed: full blood count (FBC) C-reactive protein (CRP), urine cytology and bacteriology, and cervical swab. A calcium-channel blocker tocolytic (nicardipine) at a dose of 50 mL/hour was given intravenously. An intramuscular injection of corticosteroid (12 mg celestene chronodose; betamethasone; laboratory Schering-Plough France, Lee10
vallois Perret, France) was also given to prevent hyaline-membrane disease. For the following 4 hours, the contractions progressively diminished, there was no modification in the cervix, and the FHR remained stable with slight variability on a baseline of 140 bpm. The patient was closely monitored during the following 18 hours in the delivery room and then in the pathologic pregnancy department. The tocolytic was stopped at the 24th hour. The patient was transferred to the psychiatry department after 3 days of surveillance. The obstetrical and maternal follow-up was then normal. The patient was confined naturally at 37 weeks 4 days of amenorrhea. The first 24 hours after the birth were marked by an extreme agitation of the child, who was hospitalized in neonatology. The child did not present respiratory distress, renal failure, vomiting, or convulsions. Gradually this agitation disappeared, but the child persistently showed a constant irritability and a great nervousness. These symptoms had completely disappeared after 17 days, authorizing the return of the child to its residence with his mother, in whom her mental health condition was stabilized.
C OMMENT Serotonin or 5-hydroxy-tryptamine (5HT) is 1 of the principal neurotransmit-
American Journal of Obstetrics & Gynecology NOVEMBER 2008
ters of the central nervous system. It acts by binding to specific receptors in the membranes of target cells. It acts directly on the muscle of the uterus via 5-HT2a receptors and has an indirect central action via 5-HT1-like receptors on intracranial vessels. SSRIs act by increasing serotoninergic neurotransmission by selectively inhibiting the transporter responsible for serotonin reuptake. This leads to an increase in the release of serotonin in the synaptic cleft. SSRIs are better tolerated than tricyclic antidepressants, because of their low affinity for noradrenalin or dopamine transporters and even for muscarinic cholinergic receptors. SSRIs also have no significant clinical effects on hemodynamics or cardiac electrophysiology. At very high doses, SSRIs may trigger serotoninergic syndrome and even signs of anticholinergic syndrome. Serotoninergic syndrome1 is characterized by the simultaneous presence of at least 3 of the following signs: confusion, agitation, delirium, hallucinations, mania, coma, convulsions, myoclonia (the most specific sign), hyperreflexes, sweating, shivering, trembling, diarrhea, fever, or lack of motor coordination. The principal symptoms of anticholinergic syndrome are nervous disorders (agitation, delirium, slight trem-
Case Report
www.AJOG.org
FIGURE
FHR and tocography on arrival in the maternity ward
Tixier. Voluntary intoxication with SSRI and pregnancy. Am J Obstet Gynecol 2008.
bling in the extremities), mydriasis, dryness of the mucous membranes, urinary retention, constipation, and sinusal tachycardia. Apart from the classical clinical signs of acute intoxication with an SSRI, this patient presented the risk of premature delivery, which was a direct consequence of the SSRI overdose. The intense uterine contractions were the direct consequence of the accumulation of serotonin in the synaptic cleft because of the SSRI intoxication. Since the work of Minosyan et al,2 we know that the increase in the answer to serotonin in the rat at the end of the pregnancy is related to an increase in the number of specific 5HT2a receptors rather than to an increase in their sensitivity. Calcium-channel blocker tocolytics act peripherally by blocking the voltagedependent calcium channels in the smooth muscle fibers of the uterus. In the present case, the treatment was
quickly effective. In the case of overdose in the third trimester of pregnancy, it is therefore useful to implement immediate preventive tocolysis to reduce the strength of uterine contractions. Tocometry must be maintained during the first 12-24 hours following ingestion. Even if there are doubts about the quantity ingested, tocolysis must be started, especially because the levels of the SSRI are not measured routinely. The transplacental transfer of escitalopram has been studied in isolated human placentae.3 In comparison with fluoxetine, desmethylcitalopram, an active citalopram metabolite, had significantly slower placental transfer. But in the case of overdose of citalopram, the placental barrier is probably insufficient, and a fetal repercussion is possible. This explains the variability in the FHR. These anomalies in the FHR, unless they become more serious (onset of variable, late, or prolonged slowing; or
tachycardia), must not lead to an emergency cesarean because, in the case of premature birth, management of the newly born infant will be complicated by the onset of severe withdrawal symptoms. Moreover, therapy to prevent hyaline membrane disease must be implemented immediately, especially as the risk of neonatal respiratory distress induced by an SSRI is particularly high,4-6 and there is a risk of persistent pulmonary hypertension.7 The mother and fetus must be monitored closely for the first 24-48 hours. The use of SSRI antidepressants during pregnancy is possible and, if doses are respected, does not seem to trigger neonatal complications,8-10 but the indications must be followed rigorously, and the patient must be followed up closely. However, in the literature, adverse effects in neonates exposed prenatally to escitalopram have been described,11-13 including respiratory distress, irritabil-
NOVEMBER 2008 American Journal of Obstetrics & Gynecology
e11
Case Report ity, vomiting, and convulsions. Typically these symptoms are mild and disappear by 2 weeks of age. Finally, any expectant mother under treatment with an SSRI must have regular gynecological examinations, because cases of serotoninergic syndrome have already been described for normal doses of the drug.14
C ONCLUSION In case of an overdose of an SSRI in the third trimester of pregnancy, tocolysis must be performed systematically. FHR abnormalities because of fetal intoxication must be accepted as long as they remain slight, because neonatal withdrawal symptoms could be difficult to manage. The mother and fetus must be monitored closely during the first 24-48 hours. Expectant mothers under treatment with an SSRI must have regular gynecological examinations. f ACKNOWLEDGMENT We thank Philip Bastable for help in revising the manuscript.
e12
www.AJOG.org REFERENCES 1. Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005;352:1112-20. 2. Minosyan TY, Lu R, Eghbali M, Toro L, Stefani E. Increased 5-HT contractile response in late pregnant rat myometrium is associated with a higher density of 5-HT2A receptors. J Physiol 2007;581:91-7. 3. Heikkine T, Ekblad U, Laine K. Transplacental transfer of citalopram, fluoxetine and their primary demethylated metabolites in isolated perfused human placenta. BJOG 2002; 109:1003-8. 4. Hendrick V, Smith LM, Suri R, Hwang S, Haynes D, Altshuler L. Birth outcomes after prenatal exposure to antidepressant medication. Am J Obstet Gynecol 2003;188:812-5. 5. Nordeng H, Spigset O. Treatment with selective serotonin reuptake inhibitors in the third trimester of pregnancy: effects on the infant. Drug Saf 2005;28:565-81. 6. Oberlander TF, Warburton W, Misri S, Aghajanian J, Hertzman C. Neonatal outcomes after prenatal exposure to selective serotonin reuptake inhibitor antidepressants and maternal depression using population-based linked health data. Arch Gen Psychiatry 2006;63: 898-906. 7. Chambers CD, Hernandez-Diaz S, Van Marter LJ, et al. Selective serotonin-reuptake inhibitors and risk of persistent pulmonary hypertension of the newborn. N Engl J Med 2006; 354:579-87.
American Journal of Obstetrics & Gynecology NOVEMBER 2008
8. Malm H, Klaukka T, Neuvonen PJ. Risks associated with selective serotonin reuptake inhibitors in pregnancy. Obstet Gynecol 2005; 106:1289-96. 9. Way CM. Safety of newer antidepressants in pregnancy. Pharmacotherapy 2007;27: 546-52. 10. Alwan S, Reefhuis J, Rasmussen SA, Olney RS, Friedman JM. Use of selective serotoninreuptake inhibitors in pregnancy and the risk of birth defects. N Engl J Med 2007;356: 2684-92. 11. Laine K, Heikkinen T, Ekblad U, Kero P. Effects of exposure to selective serotonin reuptake inhibitors during pregnancy on serotonergic symptoms in newborns and cord blood monoamine and prolactin concentrations. Arch Gen Psychiatry 2003;60:720-6. 12. Moses-Kolko EL, Bogen D, Perel J, et al. Neonatal signs after late in utero exposure to serotonin reuptake inhibitors: literature review and implications for clinical applications. JAMA 2005;293:2372-83. 13. Sivojelezova A, Shuhaiber S, Sarkissian L, Einarson A, Koren G. Citalopram use in pregnancy: prospective comparative evaluation of pregnancy and fetal outcome. Am J Obstet Gynecol 2005;193:2004-9. 14. Paruchuri P, Godkar D, Anandacoomarswamy D, Sheth K, Niranjan S. Rare case of serotonin syndrome with therapeutic doses of paroxetine. Am J Ther 2006;13:550-2.