LETTERS
TO
Thérapie 2015 Mai-Juin; 70 (3): 301–303 DOI: 10.2515/therapie/2014214
EDITOR
© 2014 Société Française de Pharmacologie et de Thérapeutique
Alteration of the Fetal Heart Rate Pattern Induced by the Use Of Clozapine during Pregnancy Laurie Guyon1, Marine Auffret2, Marion Coussemacq2, Johana Béné2, Philippe Deruelle1,3 and Sophie Gautier2,3 1 Department of Obstetrics and Gynecology, Hôpital Jeanne de Flandre, CHRU, Lille, France 2 Regional Center of Pharmacovigilance, CHRU, Lille, France 3 Faculty of Medicine Henri Warembourg, Université Lille 2, Lille Nord de France, Lille, France Text received August 26th, 2014; accepted October 6th, 2014 Registry number into the French national pharmacovigilance database: LL20080067 This case has been notified on the February 6th, 2008 to the Regional Center of Pharmacovigilance of Lille Abstract – Patients treated with clozapine show autonomic dysregulation and cardiac repolarisation changes. As clozapine crosses the placenta, it could have an impact on the fetus heart rate. We reported a case of reduction of the fetal heart rate variability in a patient treated with clozapine during her pregnancy. This anomaly disappeared with fetal maturation and it did not jeopardize the fetal well-being. This side effect had already been described and pharmacologists and obstetricians should be aware that clozapine may be responsible for these fetal heart rate alterations. Keywords: clozapine; fetus heart rate; pregnancy Résumé – Modification de la fréquence cardiaque fœtale induite par l'utilisation de la clozapine au cours de la grossesse. Les patients traités par clozapine présentent parfois des modifications du rythme cardiaque. Cette molécule passe le placenta et peut donc entraîner une anomalie du rythme cardiaque fœtal. Nous rapportons un cas de réduction de la variabilité du rythme cardiaque fœtal mis en évidence chez une patiente traitée par clozapine pendant sa grossesse. Cet effet indésirable, déjà rapporté par quelques auteurs, mérite d’être connu des obstétriciens et pharmacologues. Mots clés : clozapine ; rythme cardiaque fœtal ; grossesse Abreviations: see end of article.
1. Introduction Clozapine is an atypic antipsychotic used to treat schizophrenic patients. Clozapine is characterised by a high inhibition action on dopaminergic (D4), alphadrenergic, cholinergic and serotoninergic receptors. Clozapine is known to induce cardiac disorders:[1] tachycardia, bradycardia, hypotension, electrocardiography (ECG) modifications, ventricular fibrillation, myocardic and pericardic diseases and a reduced heart rate variability in a small clinical study,[2] needed to be confirmed in larger series. Very few studies were led to evaluate effects of clozapine on the fetus, but clozapine crosses the placenta and may accumulate into the foetus, which can induce side effects.[3] We report here a case of alteration of the fetal heart rate in a woman treated with clozapine.
2. Case report A 37 year-old woman, was first referred to our hospital at 32 weeks’ gestation (WG) for a second pregnancy. She had a history of schizophrenia treated with clozapine for 9 years at the dose of 125 mg per day. She also had a history of mild goiter treated with levothyroxin, 25 µg per day, because of slightly reduced levels of tri-iodo-thyronine (T3 = 2.5 pmol/L) and free thyroxin (T4 = 8.2 pmol/L) with a normal thyroid stimulating hormone level (TSH = 1.32 mU/ L). At 26 WG, she developed a mild gestational diabetes that was successfully managed with diet. The pregnancy was otherwise uneventful and the treatment remained unchanged until delivery. She was regularly seen in our outpatient clinic for diabetes management. At each follow-up visit, an obstetrical ultrasound was performed and the fetal heart rate was recorded with both conventional and computerized monitors. The ultrasound examinations showed normal anatomic development, fetal growth and vitality. The uterine and umbilical doppler studies were normal as well. The first fetal heart rate recording, made at 32 WG, showed anomalies consisting of a low variability with a normal baseline and accelerations (figure 1a). The tracing progressively normalized from 38 WG to term (figure 1b, 1c). The short term variability measurement, taken by computerized fetal heart rate analysis, was 3.5 ms at 32 and 34 WG. Its value tended to increase with gestational age (figure 1d). The patient finally delivered vaginally, 5 days after term, a healthy boy weighing 3490 g. Apgar score was 9 and 10 at 1 and 5 minutes respectively. Pediatric examination was normal 5 and 10 days after birth and the neonate didn’t require further cardiac investigations. The systematic screening for neonatal metabolic disorders, including hypothyroidism, was negative.
Article publié par EDP Sciences
© Société Française de Pharmacologie et de Thérapeutique
c
d
Fig. 1. Fetal heart rate tracing observed on cardiotocography: at 32 WG (a), 38 WG (b) and at term (c). Short term variability values during the third trimester (d). WG : gestional age.
b
a
302 Guyon et al.
Thérapie 2015 Mai-Juin; 70 (3)
Alteration of the Fetal Heart Rate Pattern
3. Discussion Most of the studies about clozapine have been conducted in adults and showed that it could cause electrocardiogram anomalies, including reduction of heart rate variability.[4] As clozapine crosses the placenta, it may be responsible for similar side-effects on the fetus. Four cases of fetal heart rate alteration in fetus whose mother was treated with clozapine have been reported in the literature:[5-7] one case observed between 34 and 37 WG, the term of delivery; one case observed at 34 WG + 5 days with a normalization when clozapine was stopped (at 35 WG + 5 days) and a recurrence of heart rate alteration when clozapine was reintroduced; one case observed at the moment of delivery: 38 WG + 5 days and one case in the context of self poisning in late pregnancy (32 WG) that lead to a caesarean section. All mothers in these four cases delivered earlier In our case and in contrast with the four other previously described cases, it was interesting to see that the fetal heart rate anomalies progressively disappeared towards the end of the pregnancy. This can be explained by the maturation of drug elimination pathways and more likely by the maturation of the autonomic nervous system, as parasympatic activity represents the most important mechanism of heart rate variability regulation.[8] Maturity could compensate for the effect of clozapine. The decreased heart rate variability was unlikely to be due to other maternal medical conditions. Diabetes was well controlled and there was no evidence for an unbalanced thyroid function. Moreover, diabetes as well as maternal thyroid anomalies (except when responsible for severe hypothyroidism in the fetus)[9] are not known to give such alterations.
4. Conclusion This case confirms the fact that maternal treatment with clozapine can induce fetal heart rate alterations. Obstetricians managing these patients should take into account this side-effect when assessing the fetal well-being
© Société Française de Pharmacologie et de Thérapeutique
303
Conflict of interest. None. Abbreviations. ECG: electrocardiogram; Mg: milligram; mU/L: micro-unity per liter; µg: microgram; Pmol/L: picomole pr liter; t3: tri-iodo-thyronine; T4: thyroxine; TSH: thyroid stimulating hormone; WG: weeks of gestation.
References 1.
Monographie Leponex http://www.theriaque.org/ Accessed August 8th, 2014
2.
Mueck-Weymann M, Rechlin T, Ehrengut F, et al. Effects of olanzapine and clozapine upon pulse rate variability. Depress Anxiety 2002; 16(3): 93-9
3.
Barnas C, Bergant A, Hummer M, et al. Clozapine concentrations in maternal and fetal plasma, amniotic fluid, and breast milk. Am J Psychiatry 1994; 151(6): 945
4.
Rechlin T, Beck G, Weis M, et al. Correlation between clozapine concentrations and heart rate variability in schizophrenic patients. Psychopharmacol (Berl) 1998; 135: 338-41
5.
Yogev Y, Ben-Haroush A, Kaplan B. Maternal clozapine treatment and decreased fetal heart rate variability. Int J Gynaecol Obstet 2002; 79: 259-60
6.
Coston AL, Hoffmann P, Equy V, et al. Fetal heart rate variability and clozapine treatment. Gynecol Obstet Fertil 2012; 40: 549-52
7.
Novikova N, Chitnis M, Linder V, et al. Atypical antipsychotic (clozapine) self-poisoning in late pregnancy presenting with absent fetal heart rate variability without acidosis and delayed peristalsis in the newborn baby: a case report. Aust N Z J Obstet Gynaecol 2009; 49(4): 442-4
8.
Lange S, Van Leeuwen P, Geue D, et al. Influence of gestational age, heart rate, gender and time of day on fetal heart rate variability. Med Biol Eng Comput 2005; 43: 481-6
9.
Rozen A, Scheiner E. Abnormal fetal heart rate tracings and congenital fetal hypothyroidism. Int J Fertil Womens Med 2006; 51: 267-9
Correspondence and offprints: Marine Auffret, Centre Régional de Pharmacovigilance, Service de Pharmacologie, CHRU, Faculté de médecine, 1 place de Verdun, CS70001, 59037 Lille cedex, France. E-mail: [email protected]
Thérapie 2015 Mai-Juin; 70 (3)
TO
Thérapie 2015 Mai-Juin; 70 (3): 301–303 DOI: 10.2515/therapie/2014214
EDITOR
© 2014 Société Française de Pharmacologie et de Thérapeutique
Alteration of the Fetal Heart Rate Pattern Induced by the Use Of Clozapine during Pregnancy Laurie Guyon1, Marine Auffret2, Marion Coussemacq2, Johana Béné2, Philippe Deruelle1,3 and Sophie Gautier2,3 1 Department of Obstetrics and Gynecology, Hôpital Jeanne de Flandre, CHRU, Lille, France 2 Regional Center of Pharmacovigilance, CHRU, Lille, France 3 Faculty of Medicine Henri Warembourg, Université Lille 2, Lille Nord de France, Lille, France Text received August 26th, 2014; accepted October 6th, 2014 Registry number into the French national pharmacovigilance database: LL20080067 This case has been notified on the February 6th, 2008 to the Regional Center of Pharmacovigilance of Lille Abstract – Patients treated with clozapine show autonomic dysregulation and cardiac repolarisation changes. As clozapine crosses the placenta, it could have an impact on the fetus heart rate. We reported a case of reduction of the fetal heart rate variability in a patient treated with clozapine during her pregnancy. This anomaly disappeared with fetal maturation and it did not jeopardize the fetal well-being. This side effect had already been described and pharmacologists and obstetricians should be aware that clozapine may be responsible for these fetal heart rate alterations. Keywords: clozapine; fetus heart rate; pregnancy Résumé – Modification de la fréquence cardiaque fœtale induite par l'utilisation de la clozapine au cours de la grossesse. Les patients traités par clozapine présentent parfois des modifications du rythme cardiaque. Cette molécule passe le placenta et peut donc entraîner une anomalie du rythme cardiaque fœtal. Nous rapportons un cas de réduction de la variabilité du rythme cardiaque fœtal mis en évidence chez une patiente traitée par clozapine pendant sa grossesse. Cet effet indésirable, déjà rapporté par quelques auteurs, mérite d’être connu des obstétriciens et pharmacologues. Mots clés : clozapine ; rythme cardiaque fœtal ; grossesse Abreviations: see end of article.
1. Introduction Clozapine is an atypic antipsychotic used to treat schizophrenic patients. Clozapine is characterised by a high inhibition action on dopaminergic (D4), alphadrenergic, cholinergic and serotoninergic receptors. Clozapine is known to induce cardiac disorders:[1] tachycardia, bradycardia, hypotension, electrocardiography (ECG) modifications, ventricular fibrillation, myocardic and pericardic diseases and a reduced heart rate variability in a small clinical study,[2] needed to be confirmed in larger series. Very few studies were led to evaluate effects of clozapine on the fetus, but clozapine crosses the placenta and may accumulate into the foetus, which can induce side effects.[3] We report here a case of alteration of the fetal heart rate in a woman treated with clozapine.
2. Case report A 37 year-old woman, was first referred to our hospital at 32 weeks’ gestation (WG) for a second pregnancy. She had a history of schizophrenia treated with clozapine for 9 years at the dose of 125 mg per day. She also had a history of mild goiter treated with levothyroxin, 25 µg per day, because of slightly reduced levels of tri-iodo-thyronine (T3 = 2.5 pmol/L) and free thyroxin (T4 = 8.2 pmol/L) with a normal thyroid stimulating hormone level (TSH = 1.32 mU/ L). At 26 WG, she developed a mild gestational diabetes that was successfully managed with diet. The pregnancy was otherwise uneventful and the treatment remained unchanged until delivery. She was regularly seen in our outpatient clinic for diabetes management. At each follow-up visit, an obstetrical ultrasound was performed and the fetal heart rate was recorded with both conventional and computerized monitors. The ultrasound examinations showed normal anatomic development, fetal growth and vitality. The uterine and umbilical doppler studies were normal as well. The first fetal heart rate recording, made at 32 WG, showed anomalies consisting of a low variability with a normal baseline and accelerations (figure 1a). The tracing progressively normalized from 38 WG to term (figure 1b, 1c). The short term variability measurement, taken by computerized fetal heart rate analysis, was 3.5 ms at 32 and 34 WG. Its value tended to increase with gestational age (figure 1d). The patient finally delivered vaginally, 5 days after term, a healthy boy weighing 3490 g. Apgar score was 9 and 10 at 1 and 5 minutes respectively. Pediatric examination was normal 5 and 10 days after birth and the neonate didn’t require further cardiac investigations. The systematic screening for neonatal metabolic disorders, including hypothyroidism, was negative.
Article publié par EDP Sciences
© Société Française de Pharmacologie et de Thérapeutique
c
d
Fig. 1. Fetal heart rate tracing observed on cardiotocography: at 32 WG (a), 38 WG (b) and at term (c). Short term variability values during the third trimester (d). WG : gestional age.
b
a
302 Guyon et al.
Thérapie 2015 Mai-Juin; 70 (3)
Alteration of the Fetal Heart Rate Pattern
3. Discussion Most of the studies about clozapine have been conducted in adults and showed that it could cause electrocardiogram anomalies, including reduction of heart rate variability.[4] As clozapine crosses the placenta, it may be responsible for similar side-effects on the fetus. Four cases of fetal heart rate alteration in fetus whose mother was treated with clozapine have been reported in the literature:[5-7] one case observed between 34 and 37 WG, the term of delivery; one case observed at 34 WG + 5 days with a normalization when clozapine was stopped (at 35 WG + 5 days) and a recurrence of heart rate alteration when clozapine was reintroduced; one case observed at the moment of delivery: 38 WG + 5 days and one case in the context of self poisning in late pregnancy (32 WG) that lead to a caesarean section. All mothers in these four cases delivered earlier In our case and in contrast with the four other previously described cases, it was interesting to see that the fetal heart rate anomalies progressively disappeared towards the end of the pregnancy. This can be explained by the maturation of drug elimination pathways and more likely by the maturation of the autonomic nervous system, as parasympatic activity represents the most important mechanism of heart rate variability regulation.[8] Maturity could compensate for the effect of clozapine. The decreased heart rate variability was unlikely to be due to other maternal medical conditions. Diabetes was well controlled and there was no evidence for an unbalanced thyroid function. Moreover, diabetes as well as maternal thyroid anomalies (except when responsible for severe hypothyroidism in the fetus)[9] are not known to give such alterations.
4. Conclusion This case confirms the fact that maternal treatment with clozapine can induce fetal heart rate alterations. Obstetricians managing these patients should take into account this side-effect when assessing the fetal well-being
© Société Française de Pharmacologie et de Thérapeutique
303
Conflict of interest. None. Abbreviations. ECG: electrocardiogram; Mg: milligram; mU/L: micro-unity per liter; µg: microgram; Pmol/L: picomole pr liter; t3: tri-iodo-thyronine; T4: thyroxine; TSH: thyroid stimulating hormone; WG: weeks of gestation.
References 1.
Monographie Leponex http://www.theriaque.org/ Accessed August 8th, 2014
2.
Mueck-Weymann M, Rechlin T, Ehrengut F, et al. Effects of olanzapine and clozapine upon pulse rate variability. Depress Anxiety 2002; 16(3): 93-9
3.
Barnas C, Bergant A, Hummer M, et al. Clozapine concentrations in maternal and fetal plasma, amniotic fluid, and breast milk. Am J Psychiatry 1994; 151(6): 945
4.
Rechlin T, Beck G, Weis M, et al. Correlation between clozapine concentrations and heart rate variability in schizophrenic patients. Psychopharmacol (Berl) 1998; 135: 338-41
5.
Yogev Y, Ben-Haroush A, Kaplan B. Maternal clozapine treatment and decreased fetal heart rate variability. Int J Gynaecol Obstet 2002; 79: 259-60
6.
Coston AL, Hoffmann P, Equy V, et al. Fetal heart rate variability and clozapine treatment. Gynecol Obstet Fertil 2012; 40: 549-52
7.
Novikova N, Chitnis M, Linder V, et al. Atypical antipsychotic (clozapine) self-poisoning in late pregnancy presenting with absent fetal heart rate variability without acidosis and delayed peristalsis in the newborn baby: a case report. Aust N Z J Obstet Gynaecol 2009; 49(4): 442-4
8.
Lange S, Van Leeuwen P, Geue D, et al. Influence of gestational age, heart rate, gender and time of day on fetal heart rate variability. Med Biol Eng Comput 2005; 43: 481-6
9.
Rozen A, Scheiner E. Abnormal fetal heart rate tracings and congenital fetal hypothyroidism. Int J Fertil Womens Med 2006; 51: 267-9
Correspondence and offprints: Marine Auffret, Centre Régional de Pharmacovigilance, Service de Pharmacologie, CHRU, Faculté de médecine, 1 place de Verdun, CS70001, 59037 Lille cedex, France. E-mail: [email protected]
Thérapie 2015 Mai-Juin; 70 (3)
