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Pregnancy and delivery under the MELAS mutation
Pregnancy and delivery under the MELAS mutation Josef Finsterer, Marlies Frank PII: DOI: Reference:
S1567-7249(16)30005-8 doi: 10.1016/j.mito.2016.02.002 MITOCH 1063
To appear in:
Mitochondrion
Received date: Revised date: Accepted date:
28 October 2015 13 November 2015 12 February 2016
Please cite this article as: Finsterer, Josef, Frank, Marlies, Pregnancy and delivery under the MELAS mutation, Mitochondrion (2016), doi: 10.1016/j.mito.2016.02.002
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.
ACCEPTED MANUSCRIPT
Pregnancy and delivery under the MELAS mutation Josef Finsterer, MD, PhD [1], Marlies Frank, MD [2]
NU MA
ED
Number of authors: 2 Number of words (abstract): 0 Number of words (body): 369 Number of references: 5 Number of tables: 0 Number of figures: 0
SC
RI P
T
[1] Krankenanstalt Rudolfstiftung, [2] First Medical Department, Krankenanstalt Rudolfstiftung, Vienna, Austria
PT
There are no conflicts of interest
AC CE
Key words: mitochondrial disorder, multisystem, mtDNA, phenotype, genotype, delivery, pregnancy, placenta
Corresponding author: Josef Finsterer, MD, PhD Postfach 20 1180 Vienna Austria, Europe Tel. +43-1-71165-92085 Fax. +43-1-4781711 E-mail: [email protected]
ACCEPTED MANUSCRIPT Letter to the Editor
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With interest we read the report by de Laat el. al. about 46 females carrying the m.3243A>G mutation who had altogether 98 pregnancies [1]. We have the following questions, comments, and concerns. Stroke-like episodes, migraine, epilepsy, arrhythmias, or heart failure are frequent clinical manifestations of MELAS [2]. In how many females was the previous history positive for any of these manifestations? How many developed any of these manifestations during pregnancy or delivery? How many had a previous pregnancy or delivery and in how many were previous obstetric complications reported? In how many multipara was the mutation known already at previous pregnancies? How many agreed to become pregnant despite being aware of the consequences? Mitochondrion-toxic drugs may strongly influence the outcome of a MELAS pregnancy. Did the authors ask for the medication taken during pregnancy? How many had epilepsy and were taking antiepileptic drugs? How many took drugs for heart failure, arrhythmias, hypertension, or for migraine-like headache? Complications during general anesthesia have been previously reported in patients with mitochondrial disorders [3,4]. How many developed adverse reactions to general anesthesia for Cesarean section? It is conceivable that those more severely affected may have more complications than those only mildly affected. Did the rate and severity of complications during pregnancy or delivery increase with increasing heteroplasmy rates? Was there any correlation between the Newcastle Mitochondrial Disease Adult Scale (NMDAS) and the rate or severity of complications? Were those with high heteroplasmy rates also those more severely affected? The authors do not mention how many of the 98 offspring carried the m.3243A>G mutation. Did any develop clinical stigmata of MELAS during pregnancy or during post-natal follow-up? Indication for premature termination of pregnancy was always the child [1]. Did those with preterm delivery also have a worse outcome after delivery? The authors mention that placental tissue is exposed to enormous oxidative stress, which may increase with progression of pregnancy [1]. Did they look for heteroplasmy rates in placental tissue and was it increased compared to heteroplasmy rates in other tissues? Was placental insufficiency correlated with placental heteroplasmy rates? 2
ACCEPTED MANUSCRIPT
AC CE
PT
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MA
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RI P
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Overall, this interesting study merits attention and comprehensive discussion to reduce complication rates during pregnancy and delivery in females carrying the m3243A>G mutation.
3
ACCEPTED MANUSCRIPT References
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1 de Laat P, Fleuren LH, Bekker MN, Smeitink JA, Janssen MC. Obstetric complications in carriers of the m.3243A > G mutation, a retrospective cohort study on maternal and fetal outcome. Mitochondrion 2015 Oct 8. pii: S1567-7249(15)30029-5. doi: 10.1016/j.mito.2015.10.005.
RI P
2 Finsterer J. Manifestations of the mitochondrial A3243G mutation. Int J Cardiol 2009;137:60-2.
SC
3 Finsterer J, Stratil U, Bittner R, Sporn P. Increased sensitivity to rocuronium and atracurium in mitochondrial myopathy. Can J Anaesth 1998;45:781-4.
NU
4 Shipton EA, Prosser DO. Mitochondrial myopathies and anaesthesia. Eur J Anaesthesiol 2004;21:173-8.
AC CE
PT
ED
MA
5 Hollingsworth KG, Gorman GS, Trenell MI, McFarland R, Taylor RW, Turnbull DM, MacGowan GA, Blamire AM, Chinnery PF. Cardiomyopathy is common in patients with the mitochondrial DNA m.3243A>G mutation and correlates with mutation load. Neuromuscul Disord 2012;22:592-6.
4
S1567-7249(16)30005-8 doi: 10.1016/j.mito.2016.02.002 MITOCH 1063
To appear in:
Mitochondrion
Received date: Revised date: Accepted date:
28 October 2015 13 November 2015 12 February 2016
Please cite this article as: Finsterer, Josef, Frank, Marlies, Pregnancy and delivery under the MELAS mutation, Mitochondrion (2016), doi: 10.1016/j.mito.2016.02.002
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.
ACCEPTED MANUSCRIPT
Pregnancy and delivery under the MELAS mutation Josef Finsterer, MD, PhD [1], Marlies Frank, MD [2]
NU MA
ED
Number of authors: 2 Number of words (abstract): 0 Number of words (body): 369 Number of references: 5 Number of tables: 0 Number of figures: 0
SC
RI P
T
[1] Krankenanstalt Rudolfstiftung, [2] First Medical Department, Krankenanstalt Rudolfstiftung, Vienna, Austria
PT
There are no conflicts of interest
AC CE
Key words: mitochondrial disorder, multisystem, mtDNA, phenotype, genotype, delivery, pregnancy, placenta
Corresponding author: Josef Finsterer, MD, PhD Postfach 20 1180 Vienna Austria, Europe Tel. +43-1-71165-92085 Fax. +43-1-4781711 E-mail: [email protected]
ACCEPTED MANUSCRIPT Letter to the Editor
AC CE
PT
ED
MA
NU
SC
RI P
T
With interest we read the report by de Laat el. al. about 46 females carrying the m.3243A>G mutation who had altogether 98 pregnancies [1]. We have the following questions, comments, and concerns. Stroke-like episodes, migraine, epilepsy, arrhythmias, or heart failure are frequent clinical manifestations of MELAS [2]. In how many females was the previous history positive for any of these manifestations? How many developed any of these manifestations during pregnancy or delivery? How many had a previous pregnancy or delivery and in how many were previous obstetric complications reported? In how many multipara was the mutation known already at previous pregnancies? How many agreed to become pregnant despite being aware of the consequences? Mitochondrion-toxic drugs may strongly influence the outcome of a MELAS pregnancy. Did the authors ask for the medication taken during pregnancy? How many had epilepsy and were taking antiepileptic drugs? How many took drugs for heart failure, arrhythmias, hypertension, or for migraine-like headache? Complications during general anesthesia have been previously reported in patients with mitochondrial disorders [3,4]. How many developed adverse reactions to general anesthesia for Cesarean section? It is conceivable that those more severely affected may have more complications than those only mildly affected. Did the rate and severity of complications during pregnancy or delivery increase with increasing heteroplasmy rates? Was there any correlation between the Newcastle Mitochondrial Disease Adult Scale (NMDAS) and the rate or severity of complications? Were those with high heteroplasmy rates also those more severely affected? The authors do not mention how many of the 98 offspring carried the m.3243A>G mutation. Did any develop clinical stigmata of MELAS during pregnancy or during post-natal follow-up? Indication for premature termination of pregnancy was always the child [1]. Did those with preterm delivery also have a worse outcome after delivery? The authors mention that placental tissue is exposed to enormous oxidative stress, which may increase with progression of pregnancy [1]. Did they look for heteroplasmy rates in placental tissue and was it increased compared to heteroplasmy rates in other tissues? Was placental insufficiency correlated with placental heteroplasmy rates? 2
ACCEPTED MANUSCRIPT
AC CE
PT
ED
MA
NU
SC
RI P
T
Overall, this interesting study merits attention and comprehensive discussion to reduce complication rates during pregnancy and delivery in females carrying the m3243A>G mutation.
3
ACCEPTED MANUSCRIPT References
T
1 de Laat P, Fleuren LH, Bekker MN, Smeitink JA, Janssen MC. Obstetric complications in carriers of the m.3243A > G mutation, a retrospective cohort study on maternal and fetal outcome. Mitochondrion 2015 Oct 8. pii: S1567-7249(15)30029-5. doi: 10.1016/j.mito.2015.10.005.
RI P
2 Finsterer J. Manifestations of the mitochondrial A3243G mutation. Int J Cardiol 2009;137:60-2.
SC
3 Finsterer J, Stratil U, Bittner R, Sporn P. Increased sensitivity to rocuronium and atracurium in mitochondrial myopathy. Can J Anaesth 1998;45:781-4.
NU
4 Shipton EA, Prosser DO. Mitochondrial myopathies and anaesthesia. Eur J Anaesthesiol 2004;21:173-8.
AC CE
PT
ED
MA
5 Hollingsworth KG, Gorman GS, Trenell MI, McFarland R, Taylor RW, Turnbull DM, MacGowan GA, Blamire AM, Chinnery PF. Cardiomyopathy is common in patients with the mitochondrial DNA m.3243A>G mutation and correlates with mutation load. Neuromuscul Disord 2012;22:592-6.
4