1
Supplementary material:
Principles for establishing causation for teratogens in humans include in addition to epidemiological studies of high quality also other data which make biological sense of the association, such as results in animal models and mechanistic information. In our previous paper we suggested a side effect of erythromycin which could explain the effect on cardiovascular defects, namely, inhibition on the most important cardiac repolarization current (Ikr). IKr is mediated by the human ether a go go gene (hERG) channel. In adult humans inhibition of the hERG channel by erythromycin results in prolongation of cardiac repolarization (manifested as prolonged QT on ECG ) and a risk for cardiac arrhythmia and sudden cardiac death [1]. A recent study shows that the hERG channel is functional and highly important for the regulation of heart rhythm (from when the tubular heart starts beating) in the human, rabbit and rat embryonic heart during organogenesis [2], see also editorial comment to the article [3]. The non-innervated embryonic heart seems to be more susceptible than the adult heart for hERG channel blockers. Several such drugs cause dose dependent teratogenicity and/or embryonic death in rats and rabbits secondary to drug induced periods of embryonic cardiac arrhythmia, resulting in hypoxia and reperfusion damage [4-5]. The embryo resists hypoxia longer than the adult organism, but it is well established in numerous studiesthat such hypoxic events are teratogenic if the embryo survives [6]. The most easily induced defects after a single dose of a potent hERG blocker in rats are cardiac septal defects; these can be induced in high frequency during the whole period of organogenesis [7];
The macrolide clarithromycin has a similar potential o block the hERG channel as erythromycin and is labelled for QT/cardiac arrhytmia risk [8]. In contrast to ertyhromycin whichwas marketed before regulatory requirements for animal teratogenicity testing were introduced, teratogenicity data are available for clarithromycin. Clarithromycin induces embryonic death in rabbits and monkeys and produces cardiovascular defects in rats [9]. In the Swedish registers, exposures for clarithromycin and other macrolides were too few to permit an evaluation of the risk of fetal adverse effects, but an increased risk for miscarriage has been reported for clarithromycin in two epidemiological studies [10,11].
Many other drugs than macrolides also have the potential for this side effect [8], however for most of these drugs insufficient information on teratogenic risks exist in humans. Currently, some of them have been associated with an increased risk for cardiovascular defects (e.g., erythromycin, clomipramine, lithium, paroxetine), while some other drugs with “QT labeling” [8] seem to lack teratogenicity (e.g., the antidepressants citalopram and sertraline) despite extensive use in pregnancy. However, in contrast to erythromycin most hERG blockers are used in a large dose span and the risk for cardiac arrhythmia in adults is negligible if the drugs are given in low doses in monotherapy. The risk increases significantly in certain situations, such as high doses or overdoses or given in combination with interacting drugs resulting in aggravated IKr inhibition [8] due to metabolic or pharmacodynamic interactions [12]. It is likely that identified risk factors for the adult heart also are relevant for the embryonic heart, and without knowledge of the doses used and more important of embryonic concentration it is difficult to estimate risk in pregnancy for an individual drug. This together with the potency to block the hERG channel and the degree of placental transfer of the drugmay contribute to explain why some drugs with QT labellingare associated with malformations and others seem to lack teratogenicity.
References
1. Ray WA, Murray KT,Meredith S, Narasimbulu SS, Hall K, Stein CM (2004) Oral erythromycin and the risk of sudden death for cardiac causes. New Engl J Med 351;1089-1096
2. Danielsson C, Brask J, Sköld AC, Genead R, Andersson A, Andersson U, Stockling K, Pehrson R, Grinnemo KH, Salari S, Hellmold H, Danielsson B, Sylvén C, Elinder F (2013) Exploration of human, rat, and rabbit embryonic cardiomyocytes suggests K-channel block as a common teratogenic mechanism. Cardiovasc Res 97:23-32
3. Franco D (2013) Wiring the developing heart: a serious matter for adulthood. Cardiovasc Res 97:4–5
4. Danielsson BR, Danielsson C, Nilsson MF (2007)Embryonic cardiac arrhythmia and generation of reactive oxygen species: common teratogenic mechanism for IKr blocking drugs
Reprod Toxicol, 24 : 42-56
5. Nilsson MF, Danielsson C, Sköld AC, Johansson A, Blomgren B, Wilson J, Khan KM, Bengtsson E, Kultima K, Webster WS, Danielsson B (2010) Improved methodology for identifying the teratogenic potential in early drug development of hERG channel blocking drugs.Reprod Toxicol, 29:156-63
6 Sköld A-C, Wellfelt K, Danielsson BR (2001) Stage-specific skeletal and visceral defects of the Ikr-blocker almokalant:.Further evidence for teratogenicity via a hypoxia-related mechanism. Teratology. 64: 292-300
7. Webster WS, Abela D (2007) The effect of hypoxia in development.Birth Defects Res C Embryo Today;81:215-28
8. Composite list of drugs that prolong QT and cause torsades de pointes (TDP) (2013). September 27, 2011.
9. Abbot Laboratories (2010) Biaxin product information.
10. Einarson A, Phillips E, Mawji F, D’Alimonte D, Schick B (1998) A prospective controlled multicentre study of clarithromycin in pregnancy. Am J Perinatol 15; 523-525
11. Andersen JT, Petersen M, Jimenez-Solem E, Broedbaek K, Andersen KL, Torp-Pedersen C, Keiding N, Enghusen Poulsen H (2013). Clarithromycin in early pregnancy and the risk of miscarraige and malformation: a register based nationwide cohort study, PLOS ONE/
12. Wenzel-Seifert K, Wittmann M, Haen E (2011) QTc prolongation by psychotropic drugs and the risk of Torsade de Pointes.Dtsch Arztebl Int. 2011 108:687-93
Supplementary Table 1: Concomitantly used drugs in women using erythromycin and whose infants had a cardiovascular defect.
Drug group / Number / Specified drugsDrugs for GERD / 1 / cimetidine
Multivitamins / 1 / -
Anticoagulants / 1 / reteplace
Folic acid / 1 / -
Glucocorticosteroids / 1 / prednisolone
Thyroxin / 1 / -
Antibiotics / 5 / doxycycline 1, tetracycline 1, phenoxymethylpenicillin 3
NSAID / 1 / ibuprofen
Analgesics / 6 / paracetamol
Hypnotics / 1 / propiomazine
Antidepressants / 1 / clomipramine
Drugs for rhinitis / 3 / phenylpropanolamine
Antiasthmatic drugs / 4 / salmeterol+fluticasone 1, budesonide 1, ipratropium 1, terbutaline 1
Cough medicines / 7 / acetylcystein 1, bromhexine 1, bromhexine+efedrine 2, ethylmorphine+coccillana+senega 3
Antihistamines / 1 / meclozine