Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome in pregnancy
- 1 Department of Obstetrics and Gynaecology, Stoke Mandeville Hospital, Aylesbury, UK
- 2 Department of Obstetrics and Gynaecology, University Hospital Southampton NHS Foundation Trust, Southampton, UK
- 3 Wessex Fetal Medicine Unit, University Hospital Southampton NHS Foundation Trust, Southampton, UK
- Correspondence to Dr Deepa Balachandran Nair; manodeepam@hotmail.com
Abstract
The syndrome of mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) is a rare mitochondrial disease with few documented cases in pregnancy. In this case report, we discuss the presentation and management of a 39-year-old grand multiparous lady with MELAS syndrome, which was diagnosed prior to her eighth pregnancy, discuss potential implications of the condition in pregnancy and summarise the current guidelines for the management of this rare condition.
Background
Around 1 in 4000 women are either at risk of developing, or have a mitochondrial mutation.1 Pregnancy is a period of high energy demand and mitochondrial disease may present then for the first time. Given the rarity of the condition, there is limited information about the effect of mitochondrial disease on pregnancy and its management, despite the association with increased maternal and fetal complications.1
Case presentation
A 39-year-old grand-multiparous mother, with seven previous uncomplicated vaginal deliveries at term, was reviewed in the local antenatal clinic. She had a significant medical history of a mitochondrial disease, which was diagnosed by formal genotyping 5 years prior, after her last pregnancy. This was following her teenage daughter being diagnosed with mitochondrial disease, which triggered testing of family members. She was found to be a carrier for the mitochondrial mutation 3243, indicative of MELAS syndrome. The patient herself had remained asymptomatic. She did not suffer from any neurological complications, including seizures, neuropathy, hearing loss, stroke-like episodes or weakness, or from endocrinopathies, including diabetes mellitus and thyroid dysfunction. Her mother and sister were diagnosed with the same mitochondrial condition, as were her other children subsequently, and they are all affected to varying degrees. Her first child sadly died from complications of the disease within 2 years of diagnosis.
Investigations
At diagnosis of MELAS syndrome, various cardiac investigations were performed to establish baseline function. An ECG showed sinus rhythm with no evidence of left ventricular hypertrophy by voltage criteria. An echocardiogram revealed normal function and dimensions of the four chambers of the heart, with no evidence of cardiomyopathy and an aortic root diameter of 2.5 cm. A cardiac MRI was also performed to screen for hypertrophic cardiomyopathy. There were normal biventricular volumes and ejection fraction, with normal wall thickness and no regional wall motion abnormalities. No evidence of overt cardiomyopathy was found. The aortic valve was trileaflet and opened well. There was no coarctation of the aorta. Pericardial thickness was normal and there was no effusion noted. A mildly dilated ascending aorta with an intraluminal measurement of 46 mm at the end of diastole was noted and surveillance was recommended. There was no evidence of hypertension. A baseline neurological examination was normal and no neurological imaging was performed.
Booking blood pressure was normal. She was commenced on aspirin as the uterine artery Doppler was predictive for pre-eclampsia or reduced fetal growth velocity. Blood pressure remained normal throughout the pregnancy, with no evidence of pre-eclampsia. An oral glucose tolerance test did not show any evidence of gestational diabetes. Further cardiac investigations were performed in the second trimester of pregnancy, including an ECG which was unremarkable and an echocardiogram which again demonstrated a dilated ascending aorta measuring 45 mm in diameter. The latter also showed mild concentric left ventricular hypertrophy, but with good overall systolic and diastolic function, with a visually estimated ejection fraction of 57%–62%, and mild aortic regurgitation. Serial fetal growth scans in the third trimester showed normal growth.
Treatment
The patient was commenced on atenolol following the echocardiogram performed in the second trimester of pregnancy. She was advised that an induction of labour and vaginal delivery could be considered at term if her cardiac function was stable. This was the patient’s preferred mode of delivery. In view of the echocardiogram findings and risk of aortic dissection associated with the dilation of the ascending aorta, she was referred to our centre for delivery—a tertiary unit for fetal and maternal medicine with a cardiothoracic unit on site. She was reviewed in the joint obstetric cardiac antenatal clinic at 35 weeks gestation and a repeat echocardiogram showed stable aortic measurements of 47 mm. She reported gradually progressive breathlessness on exertion during pregnancy and mild peripheral oedema but was generally well. Following multidisciplinary discussion between the obstetric, anaesthetic and cardiology teams, a plan for induction of labour at 37 weeks gestation to allow delivery in the tertiary centre was made, with a recommendation for early epidural analgesia. Further advice about delivery included avoiding prolonged labour, limiting the second stage of labour to 60 min and active management of third stage with slow oxytocin infusion. Ergometrine was deemed contraindicated due to the underlying cardiac pathology. If an emergency caesarean section were to be required, a regional anaesthetic would be preferable to a general anaesthetic. Other key considerations from the anaesthetic perspective included avoiding long periods of starvation, keeping warm and hydrated, monitoring for lactic acidosis, avoiding lactate containing fluids, including Hartmann’s, avoiding suxamethonium due to possibilities of myopathy and hyperkalaemia and having a regional anaesthetic where possible. She was thought to be more sensitive to non-depolarising muscle relaxants and at increased risk of paralytic ileus. Halogenated agents were deemed safe to use, with propofol and thiopentone as induction agents being safe but avoiding longer propofol infusions, preventing postoperative nausea and vomiting to limit starvation periods, avoiding aminoglycosides, sodium valproate and metformin, and considering high dependency care postnatally if required.
Outcome and follow-up
The patient presented to labour ward at 37 weeks gestation and was induced following spontaneous rupture of membranes. This was initiated with an oxytocin infusion. An epidural was sited. On admission, she had a normal full blood count with a haemoglobin of 123 g/L and platelets of 369×109/L, coagulation profile with an INR (International Normalised ratio) of 1.0 and renal profile with a creatinine of 40 μmol/L and eGFR (estimated Glomerular Filtration Rate) of >90 mL/min/1.73 m2. Her lactate levels were monitored in labour and ranged between 1.2 mmol/L and 2.6 mmol/L, glucose ranged between 3.6 mmol/L and 6.5 mmol/L and venous pH ranged between 7.369 and 7.422. She did not progress past a dilatation of 3 cm after 18 hours of oxytocin and hence had an emergency caesarean section for failed induction. A concurrent sterilisation was done at the patient’s request. The patient needed a general anaesthetic after an unsuccessful epidural top-up. The procedure was uncomplicated with a blood loss of 500 mL. Postoperative recovery was uneventful. Postnatally, atenolol was changed to bisoprolol since it was considered safer in breastfeeding. A repeat echocardiogram 3 months postpartum did not show further change in the ascending aortic diameter.
Discussion
MELAS syndrome is a rare genetic disorder affecting the mitochondria.2 It can manifest at any point in life, with the most common times for signs and symptoms to develop being between the ages of 2 years and 40 years.2 Mitochondria are responsible for 90% of energy production in the body in the form of ATP (Adenosine 5'-triphosphate) through a process of oxidative phosphorylation. They possess their own DNA, mitochondrial DNA (mtDNA)1 which is maternally inherited.3 Mutations in mtDNA can lead to alterations in energy production in various tissues, which can cause a range of clinical manifestations.1 Tissues likely to be affected are those with the highest energy demands, including the brain, heart, skeletal muscle and liver.4 The most common clinical features, therefore, include headaches, seizures, stroke-like episodes, dementia, peripheral neuropathy, sensorineural hearing loss, myopathy, endocrinopathies, including diabetes mellitus and thyroid dysfunction, and cardiac disease, including cardiomyopathy and conduction abnormalities.2
Pregnancy is a period of high energy requirements. Mitochondrial disease may manifest then for the first time and may go unrecognised if the clinician is not familiar with its clinical features.1 Additionally, the risk of complications during pregnancy and labour is thought to be increased. Reported complications include gestational diabetes, pre-eclampsia, preterm birth,1 lactic acidosis and anaesthetic risks like increased susceptibility to malignant hyperthermia, resistance or prolonged effects from muscle relaxants and hyperkalaemia with depolarising muscle relaxants.5
Eighty per cent of individuals with MELAS syndrome have been identified with a mutation in the MT-TL1 gene (m.3243A>G mutation). However, incomplete penetrance has been observed which is thought to be due to the maternal inheritance of mtDNA coupled with heteroplasmy, a variation of the number of affected mitochondria in each cell.6 For these reasons, effects on pregnancy may also vary, posing challenges for the management.3
Newcastle Guidelines on management of mitochondrial disease suggest these patients should have preconception counselling in a specialist clinic and a medication review, including the risk profile of antiepileptic and ACE inhibitors, if applicable. Folic acid supplementation is recommended as per National Institute for Health and Care Excellence (NICE) guidance. Early referral and assessment by the obstetric team and close follow-up is advised. Multidisciplinary care should be accessible to all patients with obstetric and mitochondrial medicine input. Other specialties need to be involved as required, depending on the organ systems affected by the condition. The risk of fetal growth restriction is currently uncertain, but patients are advised to have serial growth scans. An oral glucose tolerance test is also recommended in view of the higher prevalence of gestational diabetes in this group. Metformin should be avoided due to the risk of precipitating lactic acidosis. There is an increased risk of pre-eclampsia and monitoring of blood pressure and urinalysis should be performed as for a primigravid mother. Aspirin prophylaxis is not required for mitochondrial disease alone in the absence of additional risk factors for pre-eclampsia. If magnesium sulphate is required for prevention of eclampsia, monitoring for magnesium toxicity is indicated. Vaginal delivery should be encouraged in the absence of obstetric contraindications, and breastfeeding supported.1
Phenotypic variation in patients affected by MELAS syndrome results in a spectrum of effects on the different organ systems, including cardiac, neurological, muscular and metabolic. Evaluation of these systems forms an important part of the anaesthetic assessment7 and helps to provide guidance for the management of the patient preoperatively and perioperatively, allowing for risk stratification and planning.8 The Newcastle Mitochondrial Disease guidelines highlight the potential for complications to arise during this period and recommend the following: liaising with mitochondrial team for advice preoperatively allowing for specific guidance to be obtained and, therefore, risks to be minimised, avoiding prolonged periods of starvation, maintaining adequate hydration and administering all required medications during periods of fasting. There is a risk of paralytic ileus and dysmotility of the gastrointestinal system. Sodium valproate, aminoglycosides and metformin should be avoided. In case of significant respiratory muscle weakness, muscle relaxants should be avoided. Propofol is thought to be safe for induction but avoidance of infusions is recommended as they may exacerbate lactic acidosis. Fluid balance should be carefully maintained and intravenous fluids with lactate buffers avoided, for example, Ringer’s solution. Although most patients tolerate anaesthesia well, the biggest contributor to possible complications is the cardiorespiratory system. High-dependency care postoperatively should be considered.8
Aortic dilation in patients with MELAS syndrome has been described in the literature, but there is limited guidance available for its management in pregnancy. The European Society of Cardiology has published a guideline for the management of cardiovascular disease in pregnancy.9 They recommend that if aortic disease is present, women should be counselled about the risk of aortic dissection and imaging of the aorta should be performed prior to pregnancy, with CT or MRI.9 In the case of aortic dilation, there should be strict control of blood pressure with antihypertensive therapy initiated if needed.9 Ascending aortic dilation should be monitored with repeat echocardiograms every 4–12 weeks throughout pregnancy and at 6 months postpartum, with delivery in a centre with an obstetric cardiology team and cardiothoracic surgery facilities.9 If the diameter of ascending aorta is less than 40 mm, vaginal delivery would be recommended.9 A vaginal delivery with an epidural and shortened second stage would be recommended for diameters between 40 mm and 45 mm.9 If above 45 mm, a caesarean section should be considered.9 Prophylactic surgery of the aorta may be required if its diameter is over 45 mm and increasing rapidly in pregnancy.9 If the fetus is viable, delivery should be considered prior to aortic surgery.9 Pregnancy is not recommended if there is a history of aortic dissection.9
This case illustrates a rare disorder complicating pregnancy. While it brings out important aspects in the management of the condition based on available evidence, it also highlights the variations in management and anxiety the diagnosis of a condition that may not significantly alter the course of pregnancy can generate, as well as the importance of genetic counselling. This patient went through seven of her pregnancies uneventfully completely unaware of the diagnosis, but once the diagnosis was made, it became difficult for herself and the professionals looking after her to differentiate symptoms due to her pregnancy from those that might be due to the underlying condition. While maintaining a cautious approach, we managed her pregnancy based on obstetric indications unless there was a significant medical concern. We feel our experience with this patient will contribute further to the existing limited literature regarding pregnancies in women with MELAS syndrome.
Patient’s perspective
MELAS didn't affect me to a great deal during pregnancy. I was very tired throughout pregnancy and was diagnosed with a problem of my heart which was considered to be part of the MELAS. For the whole pregnancy I had check-ups and scans every 4 weeks to check baby was growing and developing properly which she was. A plan was put into place that although a c-section would be better I could try to labour and give birth naturally with induction but in a tertiary unit so specialists were available if I needed any treatment for my heart during the birth. The plan was also to only labour for 6 hours and 60 mins pushing so I didn't tire too much. I was induced and had some contractions for 18 hours but ended up having an emergency c-section under G.A. So the only symptoms I have suffered during pregnancy are fatigue, heart valve dilation and worries of baby’s growth and development. My checks by specialists in MELAS and checks on baby after birth are all normal. The baby has MELAS but until she starts to grow and reach her milestones we won't know if has any symptoms.
Learning points
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Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome is a rare mitochondrial disorder that can have a wide range of manifestations with varying implications in pregnancy.
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The most common obstetric complications reported are Gestational Diabetes Melitus (GDM), pre-eclampsia and preterm birth. Metformin is to be avoided in GDM due to increased risk of developing lactic acidosis.
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Anaesthetic considerations include avoidance of depolarising muscle relaxants and all precautions against hyperkalaemia and lactic acidosis.
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Multidisciplinary care is crucial and input from a tertiary team looking after patients with MELAS ideal given the rarity and varied presentation.
Acknowledgments
The authors thank the other medical professionals who were involved directly or indirectly in patient care, including the cardiology and anaesthetic teams at University Hospital, Southampton and the National Hospital for Neurology and Neurosurgery, London.
Footnotes
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DBN and MB are joint first authors.
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Contributors MB and DBN drafted the initial article, analysed and interpreted the case and reviewed the literature. DTH and RP revised the manuscript critically. All authors listed on the manuscript have seen and approved the submitted letter and take full responsibility for the manuscript.
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Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
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Competing interests None declared.
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Provenance and peer review Not commissioned; externally peer reviewed.
- © BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.
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