- Email: [email protected]
Abnormal pregnancy outcome associated with high-dose maternal tranylcypromine therapy: Case report and literature review
Accepted Manuscript Title: Abnormal pregnancy outcome associated with high-dose maternal tranylcypromine therapy: Case report and literature review Authors: Debra Kennedy, William S. Webster, Majella Hill, Helen E. Ritchie PII: DOI: Reference:
S0890-6238(16)30395-1 http://dx.doi.org/doi:10.1016/j.reprotox.2017.02.012 RTX 7462
To appear in:
Reproductive Toxicology
Received date: Accepted date:
19-11-2016 21-2-2017
Please cite this article as: Kennedy Debra, Webster William S, Hill Majella, Ritchie Helen E.Abnormal pregnancy outcome associated with high-dose maternal tranylcypromine therapy: Case report and literature review.Reproductive Toxicology http://dx.doi.org/10.1016/j.reprotox.2017.02.012 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Title: Abnormal pregnancy outcome associated with high-dose maternal tranylcypromine therapy: Case report and literature review
Running title: high-dose tranylcypromine during pregnancy
Debra Kennedy1,2, William S Webster3, Majella Hill1, Helen E Ritchie4
1, 2
Mothersafe, Royal Hospital for Women, Randwick NSW 2031
University of New South Wales, Randwick NSW 2031
3
Discipline of Anatomy and Histology, Sydney Medical School, University of Sydney, Sydney, NSW 2006 4
Discipline of Biomedical Science, Sydney Medical School, University of Sydney, Sydney, NSW 2114
Grants: nil Corresponding author: Debra Kennedy Royal Locked Randwick, +61412692211
Hospital
for
Women, bag
NSW,
AUS
MotherSafe 2000 2031
Telephone: +61412692211 Facsimile: +6129382 6070 [email protected]
1
Abstract BACKGROUND Tranylcypromine is a non-selective inhibitor of monamine oxidase which also inhibits the reuptake of norepinephrine. Spontaneous hypertensive reactions to the drug have been reported. In sheep tranylcypromine has been shown to cause a dose-dependent reduction in uterine blood flow. A similar effect in a pregnant woman might induce constriction of the uterine arteries and temporary fetal hypoxia. CASES MotherSafe is a state-based Teratogen Information service and currently provides counselling to around 22,000 consumers and healthcare professionals annually regarding exposures during pregnancy and breastfeeding We report on the outcome of 2 pregnancies in a patient treated with high dose tranylcypromine as well as pimozide, diazepam and alprazolam. The first pregnancy resulted in fetal death and autopsy revealed facial dysmorphism with ocular hypertelorism, cardiac defect and placental infarcts. The second pregnancy continued to term but the baby had similar dysmorphic features as well as an atrio-ventricular septal defect and craniosynostosis. CONCLUSIONS Due to their unpredictable interactions with many drugs and foods, MAO inhibitors such as tranylcypromine are not commonly used to treat depression and reports of use in pregnancy are rare. We report the outcome of 2 pregnancies with exposure to high doses of tranylcypromine resulting in children with a similar pattern of malformations. The aetiology is unknown but may relate to the vasoactive properties of the drug in above-therapeutic doses.
Keywords: maternal depression, tranylcypromine, high-dose, pregnancy outcome, fetal abnormalities
2
Introduction There are few data on the use of tranylcypromine and the other monoamine oxidase (MAO) inhibitors during human pregnancy. These drugs are rarely chosen as first line treatment due to their unpredictable interactions with many drugs and foods. The newer, selective monamine oxidase (MAO) inhibitors, such as moclobemide, have far fewer side effects and are generally well tolerated by most patients.
The Collaborative Perinatal Project monitored 21 mother-
infant pairs exposed to monamine oxidase inhibitors (including tranylcypromine, phenelzine and isoniazid) during the first trimester of pregnancy and reported 3 congenital birth defects, details of which are unavailable. Earlier, Bergamaschi and colleagues (1968) reported a case of sacrococcygeal teratoma in an infant exposed to tranylcypromine and trifluoperazine in pregnancy [1]. MotherSafe is a state-based Teratogen Information service and currently provides counselling to around 22,000 consumers and healthcare professionals annually regarding exposures during pregnancy and breastfeeding We report two pregnancies in one patient with severe depression that was not controlled by either
tricyclic
antidepressants).
antidepressants
or
selective
serotonin
reuptake
inhibitors
(SSRI
Instead during both pregnancies, she was treated daily with high dose
tranylcypromine (between 100mg and 130mg daily) as well as pimozide, diazepam and alprazolam. Case report A dysmorphic baby was referred for assessment by a Clinical Geneticist in the neonatal period. The mother was a 41-year-old lady of Lebanese descent with a long history of severe depression, which had been unresponsive to a large number of drugs. Her medications during pregnancy had been high dose tranylcypromine (between 100mg and 130mg daily), pimozide 1-2mg daily, diazepam 5-10mg daily and alprazolam 1-2mg daily. The mother had no other significant medical problems and did not smoke or drink alcohol. The father was a healthy 42-year-old man who took no medications. He was of Anglo/Scandinavian descent. The couple was not consanguineous and there was no other relevant family history. The mother's first pregnancy had been 18 months earlier. An early ultrasound scan at 11 weeks had shown a small extramembranous haemorrhage and a routine 19-week specialist obstetric ultrasound scan showed no fetal anomaly specifically no cardiac defect was noted. The mother 3
presented at 30-31 weeks’ gestation with absent fetal movements and an ultrasound showed absent fetal heart movements, and fetal measurements consistent with 28-week size, suggesting that fetal death in utero had occurred around 2 weeks previously. An autopsy was performed and revealed facial dysmorphism with ocular hypertelorism. Internal examination showed an atrio-ventricular septal defect with single coronary ostium and right pulmonary isomerism There were no other structural anomalies noted. Examination of the placenta revealed multiple infarcts which were considered significant by the pathologist in relation to the likely etiology of the fetal demise. Following her first pregnancy the mother was severely depressed and was hospitalised in a psychiatric unit for several months. Ten months after her first pregnancy she was investigated for secondary amenorrhoea and was found to be pregnant. An ultrasound scan performed at the time of the diagnosis of the pregnancy showed a fetus at around 19 weeks’ gestation with a "lemon-shaped" head. Because of the cardiac anomaly in the previous infant fetal echocardiography was performed at 26 weeks’ gestation and showed an atrio-ventricular septal defect. At 31 weeks’ gestation, an amniocentesis was performed and showed a normal female karyotype, 46, XX. Because of the past history of placental infarctions and fetal demise serial ultrasound scans were performed and these showed reduced fetal growth from 30 weeks’ gestation onwards. The mother remained on her medications, including high-dose tranylcypromine (100-120mg daily) throughout the pregnancy. Because of slowing fetal growth an elective LSCS (lower segment Caesarean section) was performed at 38 weeks’ gestation. The birth weight of the female infant was 2.6kg (10 th percentile). She was admitted to the Special Care Nursery because of respiratory distress and remained in hospital for the first few weeks of her life. Several dysmorphic features were noted including ocular hypertelorism, down slanting palpebral fissures, low-set posteriorly rotated ears with overfolded helices, upturned nose, cleft soft palate, hypoplastic distal phalanges, and pallor of the optic disc. Her cardiac defect was postnatally confirmed as an intermediate ventricular canal defect with a moderate ventricular septal defect, secundum atrial septal defect, and small patent ductus arteriosus. Agenesis of the corpus callosum was diagnosed on post-natal head ultrasound. Of note at around 2 weeks of age the baby developed abdominal distension and feed intolerance and was thought to have necrotising enterocolitis. Investigation failed to show any intestinal pathology but the symptoms resolved on cessation of breastfeeding. The abdominal symptoms were thought to be due to the presence of maternal drugs in the breastmilk. 4
Because of increasing cyanotic episodes, cardiac surgery was performed at 4 months of age. She subsequently had neurosurgery to correct sagittal craniosynostosis and to insert a ventriculo-peritoneal shunt for hydrocephalus. At age 2 years and 4 months she was still receiving gastrostomy feeds and taking pureed foods. She had global developmental delay with normal vision but some sensorineural hearing loss. At 27 months of age she was bottom shuffling but not able to walk or weight bear and could bring her hands to the midline. She attended a play group for special needs children and was receiving home-based physiotherapy, occupational therapy, and speech therapy. She now attends a special school and has severe global developmental delay. She is non–verbal, mobilises minimally independently and still cannot eat solid food. Cerebral MRI performed at the age of 5 showed complete agenesis of the corpus callosum with type 2 Arnold Chiari malformation and associated herniation of the cerebellar tonsils but no other structural anomalies were seen and it was noted that myelination had progressed and was within normal limits for age. On review by a Clinical Geneticist at age 7 she was noted to be small (<3rd percentile for weight and height) with head circumference well under the 2nd percentile. Further dysmorphic features noted were flat supraorbital margins, shallow orbits with proptosis and bilateral ptosis, high palate, micrognathia, and bilateral microtia with low-set, dysplastic and posteriorly rotated ears. The skin was soft but not hyper-elastic and vessels were seen easily through the skin. She had unusual skin mottling over the arms and legs but no other neurocutaneous stigmata. The shoulders were narrow, there was mild scoliosis and prominence of the right upper chest and the nipples were widely spaced with inversion of the left nipple. She had persistent fetal fingertip pads with hypermobility of finger joints. She has been reviewed by two Clinical Geneticists but no specific syndrome diagnosis has been made. Array CGH was performed and was reported as normal. The parents have subsequently declined further genetic investigations. MotherSafe call data In the 16 years between January 2000 and December 2015 there were 258 calls made to MotherSafe (the NSW Medications in Pregnancy and Lactation Advisory Service) regarding MAO inhibitors (compared with over 20,000 calls regarding SSRIs and tricyclic antidepressants in the same time period). 5
The majority of calls concerned the newer drug moclobemide (74%) and most callers were either pregnant or planning a future pregnancy. Of the 36 tranylcypromine calls, 20 were planning a pregnancy, six were pregnant and nine breastfeeding. The single retrospective call was regarding the patient described in this case report. In the majority of cases, calls were regarding the MAO inhibitor in association with other psychotropic medications including atypical antipsychotic medications, benzodiazepines, other antidepressants (SSRIs and tricyclic antidepressants), lithium and mood-stabilizing antiepileptic drugs. Discussion It is possible that both babies were affected by an (undiagnosed) autosomal recessive condition. Potential genetic syndrome diagnoses that were considered included Kabuki syndrome and Baller-Gerold syndrome as well as an X-linked dominant FLNA- related multiple malformation syndrome. While she shared many of the features seen in Kabuki syndrome, her craniofacial gestalt was not consistent with this diagnosis. With regard to Baller-Gerold syndrome she did not have the radial ray anomalies usually associated with this condition. The family declined further genetic testing after the normal array CGH result. Therefore, whole genome/exome sequencing or specific testing of potential genes to identify other potential causes of the phenotypes seen, including FLNA, FLNB, TGFBR1 and TGFBR2 could not be pursued. However, none of these genetic conditions would necessarily explain the significant infarcts noted in the placenta from neither the first pregnancy, nor the significant fall-off in fetal growth most likely due to placental factors seen in the second pregnancy which we postulate are related to the vascular effects of the mother’s medications. During her two pregnancies, our patient was taking up to four medications at once: tranylcypromine, pimozide, diazepam and alprazolam. It is thus possible that the adverse fetal outcomes were due to interactions between her various medications. Each of these medications has different mechanisms of action which may act directly or indirectly on the embryo. Pimozide is a diphenylbutylpiperadine that acts as a dopamine receptor blocker. It is a typical antipsychotic medication and based on animal experimental studies is not expected to significantly increase the risk of structural birth defects. The main concerns relate to the use of 6
pimozide in the latter part of pregnancy and the risk of neonatal extrapyramidal signs and adaptation symptoms such as respiratory and feeding problems [2] which would likely be exacerbated in babies exposed to multiple psychotropic drugs. However, based on studies in animals, pimozide could cause hypoxia in the fetus by slowing the fetal heart.
In adults,
pimozide is known to inhibit the Ikr channel in cardiac cells occasionally resulting in torsade des pointes [3]. Animal studies have shown that the fetal heart is highly dependent on the Ikr channel [4] and drugs, such as dofetilide, that inhibit the channel, cause severe fetal bradycardia, birth defects or embryonic death [5] similar to those seen after uterine vessel compromise [6, 7].
In vitro studies in rats have shown that pimozide decreases embryonic
heart rate at serum concentrations within therapeutic range [8] although there is a large margin of safety as it is highly protein bound [9]. Preclinical teratology studies demonstrated that pimozide induced increased embryonic death in both rats and rabbits at doses again in excess of normal therapeutic dosing [10]. The dose taken by this patient was at the lower range of therapeutic dosage providing less evidence for pimozide’s potential involvement in the child's malformations. Benzodiazepines such as diazepam and alprazolam, which this patient was also taking, have not been reported to be associated with anomalies as reported in these babies. Some (mainly retrospective) studies have suggested a slightly increased incidence of oro-facial clefting [11] but prospective studies [12, 13] have not supported this association. In addition, it is important to note that the literature reports have similar confounding factors to this case, namely multiple drug exposures. The main pharmacological effect of tranylcypromine is non-selective inhibition of monamine oxidase which is important for the breakdown of catecholamines at presynaptic terminals. During pregnancy, the uterine arteries, which take blood to the placenta, are normally maximally dilated but they are innervated by -adrenergic vasoconstrictors [14, 15]. Hence, drugs that directly or indirectly increase circulating catecholamines can potentially cause a reduction in uterine blood flow.
Examples of such drugs include cocaine, ergotamine and
epinephrine [6]. Given the activity of tranylcypromine, it is not surprising that in the pregnant sheep tranylcypromine caused a dose-dependent reduction in uterine blood flow [16]. The highest tested dose caused a 47% reduction in uterine blood flow and a 23% increase in the maternal blood pressure. The effect on uterine blood flow was prevented by pre-treatment with an -adrenergic blocking agent further implicating an adrenergic effect. Tranylcypromine has 7
also been reported to inhibit prostacyclin synthesis but alterations in this vasodilator were not detected in the study. Similarly, tranylcypromine caused significantly increased contractions in blood vessels of pregnant rabbits [17]. Spontaneous hypertensive reactions to the drug, independent of tyramine containing foods, has led to the suggestion that the drug causes indirect sympathomimetic activity or has direct -adrenergic agonist properties [18]. A similar effect in a pregnant woman would lead to preferential constriction of the uterine arteries and temporary fetal hypoxia. In both of our cases the patient was receiving a particularly high dose of tranylcypromine (up to 120 mg daily). The recommended dose is 30mg/day with caution being advised if the dose needs to be increased to a maximum of 60mg daily. Our patient was therefore receiving 2 times the recommended upper limit and up to 4 times the usual daily dose of the drug. Overdose is associated with symptoms and signs consistent with the effects of excessive norepinephrine, dopamine, and serotonin, resulting in hypertension, tachycardia, tremors, seizures and hyperthermia. Many patients tolerate even low doses of MAO inhibitors poorly. Because the patient was able to tolerate such high doses of the drug with apparently no untoward effects she took significantly higher doses than recommended. Because of the complex and unpredictable interactions between MAO inhibitors and many drugs and foods, their use has become limited to patients such as in this report with severe depression which is not controlled by the better tolerated tricyclic antidepressants or selective serotonin reuptake inhibitors (SSRI antidepressants). The newer, selective MAO inhibitors, such as moclobemide, have far fewer side effects and are generally well tolerated by most patients. The relative popularity of these medications is borne out by the MotherSafe call data. There are few data on the use of tranylcypromine and the other MAO inhibitors during human pregnancy. There have been no rigorous epidemiological studies since the Collaborative Perinatal Project published a report of 21 mother-infant pairs exposed to monamine oxidase inhibitors (including tranylcypromine, phenelzine and isoniazid) during the first trimester of pregnancy with 3 undefined congenital birth defects [19]. A single case of sacrococcygeal teratoma in an infant exposed to tranylcypromine and trifluoperazine in pregnancy had been reported previously [1]. There have been at least 3 published case reports on the use of another non-selective MAO inhibitor phenelzine (Nardil) during pregnancy, all with normal outcomes. The birth of a 8
normal male infant was reported following maternal use of phenelzine 45mg throughout pregnancy [20]. The second case involved a woman with severe depression who initially took 45 mg daily of phenelzine during pregnancy that was increased to 52.5mg for the latter half of the pregnancy. She went on to deliver a normal male infant at 37 weeks’ gestation with good Apgar scores and no structural birth defects. The child's birth weight was 2.65kg [21]. Finally, Frayne et al (2014) reported on the management and outcome of a pregnancy in a patient with a major mood disorder treated with phenelzine 105mg daily as well as lithium and quetiapine who delivered a healthy baby with a birth weight of 4.25kg and with no structural anomalies [22]. It is interesting to note that in our patient's first pregnancy the placenta was described as having multiple infarcts. Placental infarcts occurred more frequently in rats receiving iproniazid, the isopropyl derivative of the MAO inhibitor isoniazid, than in control animals [23, 24]. In our patient's second pregnancy there were clinical concerns about placental function in terms of poor fetal growth from the middle of the second trimester, although ultimately the infant's birth weight was in the lower range of normal (10th percentile). In summary, our patient was taking up to four medications at once during her two pregnancies: tranylcypromine, pimozide, diazepam and alprazolam. It is possible that the adverse fetal outcomes were due to interactions between her various medications.
However, the
psychotropic medications tranylcypromine and pimozide both have the potential to induce periods of fetal hypoxia. Animal studies have shown that intermittent hypoxia/ischemia (physically or pharmacologically induced) during the organogenic or early fetal periods can cause a range of congenital malformations. These include limb defects, particularly short or absent nails and digits, cleft palate, nasal hypoplasia, brain necrosis and dysmorphology and heart defects [5, 7, 25-31]. Our patient demonstrated distal digital hypoplasia, cleft palate as well as a cardiac defect. We postulate that fetal hypoxia/ischemia associated with reduced blood flow to the placenta is responsible for the anomalies. Although the drugs also cross the placenta and have a direct effect on the fetus, this effect appears to be minor compared with the consequences of reduced uterine circulation [32, 33].
9
Conclusion We propose that the psychotropic medications taken during these two pregnancies, particularly high-dose tranylcypromine and perhaps pimozide could have contributed to the anomalies identified in both babies. These cases demonstrate the possible effects of high doses of the MAO inhibitor tranylcypromine during human pregnancy. Because of the known vasoactive properties of the MAO inhibitor drugs, judicious use during pregnancy is warranted.
Acknowledgement: We thank Dr Lesley Adès, Clinical Geneticist Children’s Hospital Westmead, NSW for providing clinical information about the patient.
10
References [1] P. Bergamaschi, D. Berlingieri, Neuroleptic treatment at the onset of pregnancy and sacrococcygeal teratoma of the fetus, Bull Fed Soc Gynecol Obstet Lang Fr 20(5) (1968) Suppl:3168. [2] FDA Drug Safety Communication, Antipsychotic drug labels updated on use during pregnancy and risk of abnormal muscle movements and withdrawal symptoms in newborns, 2011. (Accessed 14 June 2016 2015). [3] A.H. Glassman, J.T. Bigger, Jr., Antipsychotic drugs: prolonged QTc interval, torsade de pointes, and sudden death, Am J Psychiatry 158(11) (2001) 1774-82. [4] M.P. Davies, R.H. An, P. Doevendans, S. Kubalak, K.R. Chien, R.S. Kass, M.P. Davies, R.H. An, P. Doevendans, S. Kubalak, K.R. Chien, R.S. Kass, Developmental changes in ionic channel activity in the embryonic murine heart, Circ Res 78(1) (1996) 15-25. [5] W.S. Webster, P.D. Brown-Woodman, M.D. Snow, B.R. Danielsson, Teratogenic potential of almokalant, dofetilide, and d-sotalol: drugs with potassium channel blocking activity, Teratology 53(3) (1996) 168-75. [6] B. Danielsson, W. Webster, Cardiovascular active drugs, in: Kavlock RJ, D. GP (Eds.), Drug toxicity in embryonic development II; advances in understanding mechanisms of birth defects: mechanistic understanding of human developmental toxicants, Springer, Berlin, 1997, pp. 161–90. [7] S. Spence, C. Vetter, C. Hoe, Effects of the class III antiarrhythmic, dofetilide (UK-68,798) on the heart rate of midgestation rat embryos, in vitro, Teratology 49(4) (1994) 282-92. [8] M. Gunnström, D. Ababneh, W. Webster, D. Oakes, H. Ritchie, Antipsychotic drugs cause bradycardia in GD 13 rat embryos in vitro, Repro Tox 34 (2012) 443-450. [9] A. Harmer, J.-P. Valentin, C. Pollard, On the relationship between block of the cardiac Na+ channel and drug-induced prolongation of the QRS complex, Br J Pharmacol 164 (2011) 260273. [10] Orap, Product monograph for Pimozide., MM Therapeutics Inc, Montréal, Québec, Canada, 2011. [11] I. Saxen, L. Saxen, Association between maternal intake of diazepam and oral clefts, Lancet 2(7933) (1975 ) 498. [12] A. Ornoy, J. Arnon, S. Shechtman, L. Moerman, I. Lukashova, Is benzodiazepine use during pregnancy really teratogenic?, Reprod Toxicol 12(5) (1998) 511-5. [13] A. Pastuszak, V. Milich, S. Chan, J. Chu, G. Koren, Prospective assessment of pregnancy outcome following first trimester exposure to benzodiazepines, Can J Clin Pharmacol 3 (1996) 167-171. [14] F.C. Greiss, The uterine vascular bed: effect of adrenergic stimulation, Obstet Gynecol 21 (1963) 295-301. [15] F.C. Greiss, Differential reactivity of myoendometrial and placental vasculature. Adrenergic responses., Am J Obstet Gynecol 112 (1972) 20-27. [16] K. Clark, D. Harrington, Effect of the prostacyclin synthetase inhibitor tranylcypromine on uterine blood flow in pregnancy, Prostaglandins 23 (1982) 227-36. [17] O. Nakamoto, A. Hidaka, Effect of endothelium-derived nitric oxide and prostaglandins on the endothelium-dependent vascular refractoriness to angiotensin II in pregnant rabbits., Nihon Sanka Fujinka Gakkai zasshi (44) (1992) 1149-56. [18] P.E. Keck, Jr., W.P. Carter, A.A. Nierenberg, T.B. Cooper, W.Z. Potter, A.J. Rothschild, Acute cardiovascular effects of tranylcypromine: correlation with plasma drug, metabolite, norepinephrine, and MHPG levels, J Clin Psychiatry 52(6) (1991) 250-4. 11
[19] O. Heinonen, D. Slone, S. Shapiro, Birth defects and drugs in pregnancy, Publishing Sciences group, Littleton, MA, 1977. [20] T.J. Pavy, A.P. Kliffer, M.J. Douglas, Anaesthetic managemnt of labour and delivery in a woman taking longterm MAOI. , Can J Anaesthesia 42 (1995) 618-620. [21] B.L. Gracious, K.L. Wisner, Phenelzine use throughout pregnancy and the puerperium: case report, review of the literature, and management recommendations, Depress Anxiety 6(3) (1997) 124-8. [22] J. Frayne, T. Nguyen, R. Kohan, N. De Felice, J. Rampono, The comprehensive management of pregnant women with major mood disorders: a case study involving phenelzine, lithium, and quetiapine, Archives of Womens Mental Health 17(1) (2014) 73-75. [23] E. Poulson, M. Botros, J.M. Robson, Effect of 5-hydroxytryptamine and iproniazid on pregnancy, Science 131(3407) (1960) 1101-2. [24] E. Poulson, J.M. Robson, The effect of amine oxidase inhibitors on pregnancy, J Endocrinol 27 (1963). [25] R.L. Brent, J.B. Franklin, Uterine vascular clamping: new procedure for the study of congenital malformations, Science 132(3419) (1960) 89-91. [26] J.B. Franklin, R.L. Brent, Effect of uterine vascular clamping on development of rat embryos three to fourteen days old J Morphol 115(2) (1964) 273-90. [27] J. Grauwiler, H. Schon, Teratological experiments with ergotamine in mice, rats, and rabbits, Teratology 7(3) (1973) 227-35. [28] A.C. Skold, K. Wellfelt, B.R. Danielsson, Stage-specific skeletal and visceral defects of the I(Kr)-blocker almokalant: further evidence for teratogenicity via a hypoxia-related mechanism, Teratology 64(6) (2001) 292-300. [29] W.S. Webster, P.D. Brown-Woodman, Cocaine as a cause of congenital malformations of vascular origin: experimental evidence in the rat, Teratology 41(6) (1990). [30] W.S. Webster, P.D. Brown-Woodman, A.H. Lipson, H.E. Ritchie, Fetal brain damage in the rat following prenatal exposure to cocaine, Neurotoxicol Teratol 13(6) (1991) 621-6. [31] W.S. Webster, A.H. Lipson, P.D. Brown-Woodman, Uterine trauma and limb defects, Teratology 35(2) (1987) 253-60. [32] N. Chernoff, C.T. Grabowski, Responses of the rat foetus to maternal injections of adrenaline and vasopressin, Br J Pharmacol 43(2) (1971). [33] K. Leist, J. Grauwiler, Transplacental passage of 3H ergotamine in the rat and determination of the intraamniotic embryotoxicity of ergotamine, Experientia 29 (1973) 764.
12
S0890-6238(16)30395-1 http://dx.doi.org/doi:10.1016/j.reprotox.2017.02.012 RTX 7462
To appear in:
Reproductive Toxicology
Received date: Accepted date:
19-11-2016 21-2-2017
Please cite this article as: Kennedy Debra, Webster William S, Hill Majella, Ritchie Helen E.Abnormal pregnancy outcome associated with high-dose maternal tranylcypromine therapy: Case report and literature review.Reproductive Toxicology http://dx.doi.org/10.1016/j.reprotox.2017.02.012 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Title: Abnormal pregnancy outcome associated with high-dose maternal tranylcypromine therapy: Case report and literature review
Running title: high-dose tranylcypromine during pregnancy
Debra Kennedy1,2, William S Webster3, Majella Hill1, Helen E Ritchie4
1, 2
Mothersafe, Royal Hospital for Women, Randwick NSW 2031
University of New South Wales, Randwick NSW 2031
3
Discipline of Anatomy and Histology, Sydney Medical School, University of Sydney, Sydney, NSW 2006 4
Discipline of Biomedical Science, Sydney Medical School, University of Sydney, Sydney, NSW 2114
Grants: nil Corresponding author: Debra Kennedy Royal Locked Randwick, +61412692211
Hospital
for
Women, bag
NSW,
AUS
MotherSafe 2000 2031
Telephone: +61412692211 Facsimile: +6129382 6070 [email protected]
1
Abstract BACKGROUND Tranylcypromine is a non-selective inhibitor of monamine oxidase which also inhibits the reuptake of norepinephrine. Spontaneous hypertensive reactions to the drug have been reported. In sheep tranylcypromine has been shown to cause a dose-dependent reduction in uterine blood flow. A similar effect in a pregnant woman might induce constriction of the uterine arteries and temporary fetal hypoxia. CASES MotherSafe is a state-based Teratogen Information service and currently provides counselling to around 22,000 consumers and healthcare professionals annually regarding exposures during pregnancy and breastfeeding We report on the outcome of 2 pregnancies in a patient treated with high dose tranylcypromine as well as pimozide, diazepam and alprazolam. The first pregnancy resulted in fetal death and autopsy revealed facial dysmorphism with ocular hypertelorism, cardiac defect and placental infarcts. The second pregnancy continued to term but the baby had similar dysmorphic features as well as an atrio-ventricular septal defect and craniosynostosis. CONCLUSIONS Due to their unpredictable interactions with many drugs and foods, MAO inhibitors such as tranylcypromine are not commonly used to treat depression and reports of use in pregnancy are rare. We report the outcome of 2 pregnancies with exposure to high doses of tranylcypromine resulting in children with a similar pattern of malformations. The aetiology is unknown but may relate to the vasoactive properties of the drug in above-therapeutic doses.
Keywords: maternal depression, tranylcypromine, high-dose, pregnancy outcome, fetal abnormalities
2
Introduction There are few data on the use of tranylcypromine and the other monoamine oxidase (MAO) inhibitors during human pregnancy. These drugs are rarely chosen as first line treatment due to their unpredictable interactions with many drugs and foods. The newer, selective monamine oxidase (MAO) inhibitors, such as moclobemide, have far fewer side effects and are generally well tolerated by most patients.
The Collaborative Perinatal Project monitored 21 mother-
infant pairs exposed to monamine oxidase inhibitors (including tranylcypromine, phenelzine and isoniazid) during the first trimester of pregnancy and reported 3 congenital birth defects, details of which are unavailable. Earlier, Bergamaschi and colleagues (1968) reported a case of sacrococcygeal teratoma in an infant exposed to tranylcypromine and trifluoperazine in pregnancy [1]. MotherSafe is a state-based Teratogen Information service and currently provides counselling to around 22,000 consumers and healthcare professionals annually regarding exposures during pregnancy and breastfeeding We report two pregnancies in one patient with severe depression that was not controlled by either
tricyclic
antidepressants).
antidepressants
or
selective
serotonin
reuptake
inhibitors
(SSRI
Instead during both pregnancies, she was treated daily with high dose
tranylcypromine (between 100mg and 130mg daily) as well as pimozide, diazepam and alprazolam. Case report A dysmorphic baby was referred for assessment by a Clinical Geneticist in the neonatal period. The mother was a 41-year-old lady of Lebanese descent with a long history of severe depression, which had been unresponsive to a large number of drugs. Her medications during pregnancy had been high dose tranylcypromine (between 100mg and 130mg daily), pimozide 1-2mg daily, diazepam 5-10mg daily and alprazolam 1-2mg daily. The mother had no other significant medical problems and did not smoke or drink alcohol. The father was a healthy 42-year-old man who took no medications. He was of Anglo/Scandinavian descent. The couple was not consanguineous and there was no other relevant family history. The mother's first pregnancy had been 18 months earlier. An early ultrasound scan at 11 weeks had shown a small extramembranous haemorrhage and a routine 19-week specialist obstetric ultrasound scan showed no fetal anomaly specifically no cardiac defect was noted. The mother 3
presented at 30-31 weeks’ gestation with absent fetal movements and an ultrasound showed absent fetal heart movements, and fetal measurements consistent with 28-week size, suggesting that fetal death in utero had occurred around 2 weeks previously. An autopsy was performed and revealed facial dysmorphism with ocular hypertelorism. Internal examination showed an atrio-ventricular septal defect with single coronary ostium and right pulmonary isomerism There were no other structural anomalies noted. Examination of the placenta revealed multiple infarcts which were considered significant by the pathologist in relation to the likely etiology of the fetal demise. Following her first pregnancy the mother was severely depressed and was hospitalised in a psychiatric unit for several months. Ten months after her first pregnancy she was investigated for secondary amenorrhoea and was found to be pregnant. An ultrasound scan performed at the time of the diagnosis of the pregnancy showed a fetus at around 19 weeks’ gestation with a "lemon-shaped" head. Because of the cardiac anomaly in the previous infant fetal echocardiography was performed at 26 weeks’ gestation and showed an atrio-ventricular septal defect. At 31 weeks’ gestation, an amniocentesis was performed and showed a normal female karyotype, 46, XX. Because of the past history of placental infarctions and fetal demise serial ultrasound scans were performed and these showed reduced fetal growth from 30 weeks’ gestation onwards. The mother remained on her medications, including high-dose tranylcypromine (100-120mg daily) throughout the pregnancy. Because of slowing fetal growth an elective LSCS (lower segment Caesarean section) was performed at 38 weeks’ gestation. The birth weight of the female infant was 2.6kg (10 th percentile). She was admitted to the Special Care Nursery because of respiratory distress and remained in hospital for the first few weeks of her life. Several dysmorphic features were noted including ocular hypertelorism, down slanting palpebral fissures, low-set posteriorly rotated ears with overfolded helices, upturned nose, cleft soft palate, hypoplastic distal phalanges, and pallor of the optic disc. Her cardiac defect was postnatally confirmed as an intermediate ventricular canal defect with a moderate ventricular septal defect, secundum atrial septal defect, and small patent ductus arteriosus. Agenesis of the corpus callosum was diagnosed on post-natal head ultrasound. Of note at around 2 weeks of age the baby developed abdominal distension and feed intolerance and was thought to have necrotising enterocolitis. Investigation failed to show any intestinal pathology but the symptoms resolved on cessation of breastfeeding. The abdominal symptoms were thought to be due to the presence of maternal drugs in the breastmilk. 4
Because of increasing cyanotic episodes, cardiac surgery was performed at 4 months of age. She subsequently had neurosurgery to correct sagittal craniosynostosis and to insert a ventriculo-peritoneal shunt for hydrocephalus. At age 2 years and 4 months she was still receiving gastrostomy feeds and taking pureed foods. She had global developmental delay with normal vision but some sensorineural hearing loss. At 27 months of age she was bottom shuffling but not able to walk or weight bear and could bring her hands to the midline. She attended a play group for special needs children and was receiving home-based physiotherapy, occupational therapy, and speech therapy. She now attends a special school and has severe global developmental delay. She is non–verbal, mobilises minimally independently and still cannot eat solid food. Cerebral MRI performed at the age of 5 showed complete agenesis of the corpus callosum with type 2 Arnold Chiari malformation and associated herniation of the cerebellar tonsils but no other structural anomalies were seen and it was noted that myelination had progressed and was within normal limits for age. On review by a Clinical Geneticist at age 7 she was noted to be small (<3rd percentile for weight and height) with head circumference well under the 2nd percentile. Further dysmorphic features noted were flat supraorbital margins, shallow orbits with proptosis and bilateral ptosis, high palate, micrognathia, and bilateral microtia with low-set, dysplastic and posteriorly rotated ears. The skin was soft but not hyper-elastic and vessels were seen easily through the skin. She had unusual skin mottling over the arms and legs but no other neurocutaneous stigmata. The shoulders were narrow, there was mild scoliosis and prominence of the right upper chest and the nipples were widely spaced with inversion of the left nipple. She had persistent fetal fingertip pads with hypermobility of finger joints. She has been reviewed by two Clinical Geneticists but no specific syndrome diagnosis has been made. Array CGH was performed and was reported as normal. The parents have subsequently declined further genetic investigations. MotherSafe call data In the 16 years between January 2000 and December 2015 there were 258 calls made to MotherSafe (the NSW Medications in Pregnancy and Lactation Advisory Service) regarding MAO inhibitors (compared with over 20,000 calls regarding SSRIs and tricyclic antidepressants in the same time period). 5
The majority of calls concerned the newer drug moclobemide (74%) and most callers were either pregnant or planning a future pregnancy. Of the 36 tranylcypromine calls, 20 were planning a pregnancy, six were pregnant and nine breastfeeding. The single retrospective call was regarding the patient described in this case report. In the majority of cases, calls were regarding the MAO inhibitor in association with other psychotropic medications including atypical antipsychotic medications, benzodiazepines, other antidepressants (SSRIs and tricyclic antidepressants), lithium and mood-stabilizing antiepileptic drugs. Discussion It is possible that both babies were affected by an (undiagnosed) autosomal recessive condition. Potential genetic syndrome diagnoses that were considered included Kabuki syndrome and Baller-Gerold syndrome as well as an X-linked dominant FLNA- related multiple malformation syndrome. While she shared many of the features seen in Kabuki syndrome, her craniofacial gestalt was not consistent with this diagnosis. With regard to Baller-Gerold syndrome she did not have the radial ray anomalies usually associated with this condition. The family declined further genetic testing after the normal array CGH result. Therefore, whole genome/exome sequencing or specific testing of potential genes to identify other potential causes of the phenotypes seen, including FLNA, FLNB, TGFBR1 and TGFBR2 could not be pursued. However, none of these genetic conditions would necessarily explain the significant infarcts noted in the placenta from neither the first pregnancy, nor the significant fall-off in fetal growth most likely due to placental factors seen in the second pregnancy which we postulate are related to the vascular effects of the mother’s medications. During her two pregnancies, our patient was taking up to four medications at once: tranylcypromine, pimozide, diazepam and alprazolam. It is thus possible that the adverse fetal outcomes were due to interactions between her various medications. Each of these medications has different mechanisms of action which may act directly or indirectly on the embryo. Pimozide is a diphenylbutylpiperadine that acts as a dopamine receptor blocker. It is a typical antipsychotic medication and based on animal experimental studies is not expected to significantly increase the risk of structural birth defects. The main concerns relate to the use of 6
pimozide in the latter part of pregnancy and the risk of neonatal extrapyramidal signs and adaptation symptoms such as respiratory and feeding problems [2] which would likely be exacerbated in babies exposed to multiple psychotropic drugs. However, based on studies in animals, pimozide could cause hypoxia in the fetus by slowing the fetal heart.
In adults,
pimozide is known to inhibit the Ikr channel in cardiac cells occasionally resulting in torsade des pointes [3]. Animal studies have shown that the fetal heart is highly dependent on the Ikr channel [4] and drugs, such as dofetilide, that inhibit the channel, cause severe fetal bradycardia, birth defects or embryonic death [5] similar to those seen after uterine vessel compromise [6, 7].
In vitro studies in rats have shown that pimozide decreases embryonic
heart rate at serum concentrations within therapeutic range [8] although there is a large margin of safety as it is highly protein bound [9]. Preclinical teratology studies demonstrated that pimozide induced increased embryonic death in both rats and rabbits at doses again in excess of normal therapeutic dosing [10]. The dose taken by this patient was at the lower range of therapeutic dosage providing less evidence for pimozide’s potential involvement in the child's malformations. Benzodiazepines such as diazepam and alprazolam, which this patient was also taking, have not been reported to be associated with anomalies as reported in these babies. Some (mainly retrospective) studies have suggested a slightly increased incidence of oro-facial clefting [11] but prospective studies [12, 13] have not supported this association. In addition, it is important to note that the literature reports have similar confounding factors to this case, namely multiple drug exposures. The main pharmacological effect of tranylcypromine is non-selective inhibition of monamine oxidase which is important for the breakdown of catecholamines at presynaptic terminals. During pregnancy, the uterine arteries, which take blood to the placenta, are normally maximally dilated but they are innervated by -adrenergic vasoconstrictors [14, 15]. Hence, drugs that directly or indirectly increase circulating catecholamines can potentially cause a reduction in uterine blood flow.
Examples of such drugs include cocaine, ergotamine and
epinephrine [6]. Given the activity of tranylcypromine, it is not surprising that in the pregnant sheep tranylcypromine caused a dose-dependent reduction in uterine blood flow [16]. The highest tested dose caused a 47% reduction in uterine blood flow and a 23% increase in the maternal blood pressure. The effect on uterine blood flow was prevented by pre-treatment with an -adrenergic blocking agent further implicating an adrenergic effect. Tranylcypromine has 7
also been reported to inhibit prostacyclin synthesis but alterations in this vasodilator were not detected in the study. Similarly, tranylcypromine caused significantly increased contractions in blood vessels of pregnant rabbits [17]. Spontaneous hypertensive reactions to the drug, independent of tyramine containing foods, has led to the suggestion that the drug causes indirect sympathomimetic activity or has direct -adrenergic agonist properties [18]. A similar effect in a pregnant woman would lead to preferential constriction of the uterine arteries and temporary fetal hypoxia. In both of our cases the patient was receiving a particularly high dose of tranylcypromine (up to 120 mg daily). The recommended dose is 30mg/day with caution being advised if the dose needs to be increased to a maximum of 60mg daily. Our patient was therefore receiving 2 times the recommended upper limit and up to 4 times the usual daily dose of the drug. Overdose is associated with symptoms and signs consistent with the effects of excessive norepinephrine, dopamine, and serotonin, resulting in hypertension, tachycardia, tremors, seizures and hyperthermia. Many patients tolerate even low doses of MAO inhibitors poorly. Because the patient was able to tolerate such high doses of the drug with apparently no untoward effects she took significantly higher doses than recommended. Because of the complex and unpredictable interactions between MAO inhibitors and many drugs and foods, their use has become limited to patients such as in this report with severe depression which is not controlled by the better tolerated tricyclic antidepressants or selective serotonin reuptake inhibitors (SSRI antidepressants). The newer, selective MAO inhibitors, such as moclobemide, have far fewer side effects and are generally well tolerated by most patients. The relative popularity of these medications is borne out by the MotherSafe call data. There are few data on the use of tranylcypromine and the other MAO inhibitors during human pregnancy. There have been no rigorous epidemiological studies since the Collaborative Perinatal Project published a report of 21 mother-infant pairs exposed to monamine oxidase inhibitors (including tranylcypromine, phenelzine and isoniazid) during the first trimester of pregnancy with 3 undefined congenital birth defects [19]. A single case of sacrococcygeal teratoma in an infant exposed to tranylcypromine and trifluoperazine in pregnancy had been reported previously [1]. There have been at least 3 published case reports on the use of another non-selective MAO inhibitor phenelzine (Nardil) during pregnancy, all with normal outcomes. The birth of a 8
normal male infant was reported following maternal use of phenelzine 45mg throughout pregnancy [20]. The second case involved a woman with severe depression who initially took 45 mg daily of phenelzine during pregnancy that was increased to 52.5mg for the latter half of the pregnancy. She went on to deliver a normal male infant at 37 weeks’ gestation with good Apgar scores and no structural birth defects. The child's birth weight was 2.65kg [21]. Finally, Frayne et al (2014) reported on the management and outcome of a pregnancy in a patient with a major mood disorder treated with phenelzine 105mg daily as well as lithium and quetiapine who delivered a healthy baby with a birth weight of 4.25kg and with no structural anomalies [22]. It is interesting to note that in our patient's first pregnancy the placenta was described as having multiple infarcts. Placental infarcts occurred more frequently in rats receiving iproniazid, the isopropyl derivative of the MAO inhibitor isoniazid, than in control animals [23, 24]. In our patient's second pregnancy there were clinical concerns about placental function in terms of poor fetal growth from the middle of the second trimester, although ultimately the infant's birth weight was in the lower range of normal (10th percentile). In summary, our patient was taking up to four medications at once during her two pregnancies: tranylcypromine, pimozide, diazepam and alprazolam. It is possible that the adverse fetal outcomes were due to interactions between her various medications.
However, the
psychotropic medications tranylcypromine and pimozide both have the potential to induce periods of fetal hypoxia. Animal studies have shown that intermittent hypoxia/ischemia (physically or pharmacologically induced) during the organogenic or early fetal periods can cause a range of congenital malformations. These include limb defects, particularly short or absent nails and digits, cleft palate, nasal hypoplasia, brain necrosis and dysmorphology and heart defects [5, 7, 25-31]. Our patient demonstrated distal digital hypoplasia, cleft palate as well as a cardiac defect. We postulate that fetal hypoxia/ischemia associated with reduced blood flow to the placenta is responsible for the anomalies. Although the drugs also cross the placenta and have a direct effect on the fetus, this effect appears to be minor compared with the consequences of reduced uterine circulation [32, 33].
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Conclusion We propose that the psychotropic medications taken during these two pregnancies, particularly high-dose tranylcypromine and perhaps pimozide could have contributed to the anomalies identified in both babies. These cases demonstrate the possible effects of high doses of the MAO inhibitor tranylcypromine during human pregnancy. Because of the known vasoactive properties of the MAO inhibitor drugs, judicious use during pregnancy is warranted.
Acknowledgement: We thank Dr Lesley Adès, Clinical Geneticist Children’s Hospital Westmead, NSW for providing clinical information about the patient.
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