Myotonic disorders and pregnancy

Short abstract

Myotonic disorders represent significant risk in pregnancy due to their complexity and the risk of maternal and fetal complications. Care of these pregnancies requires detailed pre-conception counselling, close monitoring of mother and fetus during the pregnancy and a delivery and postpartum plan involving a multidisciplinary team approach. A case of a woman with myotonia congenita diagnosed in pregnancy is presented, the general principles of care of women with myotonic disorders discussed, and care of the specific conditions in pregnancy reviewed.

Trial registration: Not applicable.

Introduction

The myotonic disorders are a heterogeneous group of genetic disorders manifesting failure of skeletal muscle relaxation following activation (Table 1). The myotonic dystrophies type 1 and 2 (DM1 and DM2) are by far the most common. The less common non-dystrophic myotonias include myotonia congenita (MC), paramyotonia congenita (PMC) and sodium channel myotonia (SCM). Related sodium channelopathies include hyperkalaemic periodic paralysis, hypokalaemic periodic paralysis and severe neonatal laryngospasm.

Table 1.

Summary of myotonic disorders.

	DM1	DM2	Dominant MC (Thomsen)	Recessive MC (Becker)	PMC	SCM
Incidence	1 : 10,000	1 : 10,000	1 : 25,000	1 : 25,000	1 : 100,000	1 : 400,000
Gene	DMPK	CNBP	CLCN1	CLCN1	SCN4A	SCN4A
Inheritance	AD	AD	AD	AR	AD	AD
Distribution	Face, jaw, tongue and intrinsic hand muscle	Neck, hands, elbow and hip flexors/extensors	Upper > lower limbs	Lower > upper limbs	Face, eyelids, tongue and hands	Face, eyelids, eyes, tongue, hands and legs
Weakness	Distal limbs and face	Proximal limbs	Rare	Transient on initiation activity	Proximal lower limbs	No
Triggers	Nil	Nil	Cold, rest	Cold, rest	Cold, exercise	K+ (exercise/cold depending on phenotype)
Pregnancy complications	Reduced fertility, polyhydramnios, Preterm labour, non-vertex present, instrumental delivery, placenta praevia, postpartum haemorrhage and perinatal death	UTIs, preterm labour and stillbirth			Neonatal hypotonia

DM1: myotonic dystrophy type 1; DM2: myotonic dystrophy type 2; MC: myotonia congenita; PMC: paramyotonia congenita; SCM: sodium channel myotonia; AD: autosomal dominant; AR: autosomal recessive; UTI: urinary tract infection.

Women may present with undiagnosed myotonic disorders during pregnancy, as the diagnosis is frequently missed.¹ Myotonias, particularly DM1 and DM2, have significant implications for mother and fetus (Table 1). There is no consensus regarding the recommended mode of delivery. Regional anaesthesia is preferred to general anaesthesia. Depolarising muscle relaxants are contraindicated due to the risk of malignant hyperthermia, and patients may demonstrate increased sensitivity to other anaesthetic agents leading to respiratory depression. Caution should be employed with the use of magnesium sulphate, as severe weakness and respiratory compromise have been reported in a woman with mild DM1.² Care of the woman with a myotonic disorder requires a multidisciplinary approach including obstetrician, geneticist, anaesthetist, neonatologist, physician, midwife, physiotherapist and occupational therapist.

Case report

A 35-year-old primigravida Chinese woman was reviewed in antenatal clinic at 14 weeks’ gestation. She gave a history of muscle stiffness and difficulty initiating movement after periods of immobility since early childhood. Her brother was similarly affected. No previous investigations had been performed. Physical examination revealed hypertrophy of the calf and biceps muscles bilaterally and percussion and grip myotonia. Muscle strength was normal. Electromyographic (EMG) study disclosed electrophysiological evidence of myotonic runs as well as myopathic muscle units in the right abductor pollicis brevis muscle. Genetic testing showed compound heterozygosity for two mutations (deletion of exons 1 to 23 and p.Thr268Met) in the CLCN1 gene consistent with Becker-type MC. Echocardiography and respiratory function tests were normal. The patient noted mild progression of myotonic symptoms during pregnancy. After multidisciplinary team review, induction of labour with early epidural at 38 weeks was recommended, with the patient to be kept warm throughout labour and an assisted second stage if required. The patient, however, subsequently declined induction of labour. Estimated fetal weight on ultrasound at 36 weeks’ gestation was 3529 g. The patient presented at 39.3 weeks’ gestation following spontaneous rupture of membranes. Amniotomy was commenced 24 h later when labour failed to establish, and syntocinon infusion was commenced and gradually increased to 12 iu/h. Uterine contractions were normal. In view of failure to progress, a vacuum delivery of a healthy male (birthweight 3860 g) was performed. Delivery was complicated by a second-degree vaginal tear and 1200 ml postpartum haemorrhage. The baby displayed no signs of a neuromuscular disorder and is to be followed up at neurology and genetics outpatients.

Clinical presentation of myotonic disorders

Clinical myotonia typically manifests as painless muscle stiffness, particularly affecting the eyelids, mouth, hands and proximal lower extremities.³ DM2, however, is associated with muscle pain in 60% to 80% of patients, which may be severe and misdiagnosed as fibromyalgia. Myotonia tends to improve with repeated action (warm-up phenomenon) with the exception of PMC and some phenotypes of SCM where myotonia paradoxically worsens with repeated activity.

Myotonic dystrophy

DM1 occurs due to a CTG repeat in the DMPK gene, while DM2 occurs due to a CCTG repeat in the CNBP gene.⁴ The size of the CTG repeats generally correlates with the severity and age of onset of clinical symptoms in DM1 families. In DM1, genetic anticipation may lead to expansion of the CTG repeat and more severe disease in successive generations.

DM1 classically presents in the second to fourth decade. Early cataracts, frontal balding, ptosis and temporal muscle atrophy may result in a characteristic facies (Figure 1). Weakness is typically prominent in facial muscles, neck extensors/flexors and distal limbs with a predilection for finger flexors/extensors and feet dorsiflexors. Muscle atrophy occurs proportionate to weakness. DM2 is generally associated with a milder phenotype of early cataracts, myalgias and proximal weakness involving hip flexors/extensors, neck flexors, elbow extensors and thumb/deep finger flexors. Facial weakness is less common, and marked muscle atrophy is uncommon in DM2. Clinical myotonia may be absent in 25% of DM2.

Figure 1.

Myotonic dystrophy – clinical features.

Systemic features of DM include cardiac abnormalities, respiratory muscle weakness, excessive daytime sleepiness, hearing impairment, gastrointestinal symptoms, cognitive impairment, axonal neuropathy, impaired glucose tolerance and abnormal liver function tests. In general, systemic features are less common and severe in DM2 than in DM1.¹

Non-dystrophic myotonias

Myotonia congenita

MC results from mutations in the skeletal muscle chloride channel gene (CLCN1). It occurs as autosomal dominant (Thomsen disease) and recessive (Becker disease) forms. Characteristic features of MC include the warm-up phenomenon, generalised muscle hypertrophy resulting in a “Herculean” or “bodybuilder” appearance, worsening of symptoms with exposure to cold (50%–60%) and pain (30%–50%). In autosomal dominant MC, symptoms are milder and more commonly involve the upper limbs. Muscles of mastication and swallowing may be affected. Myotonia in autosomal recessive MC tends to be more pronounced in the lower extremity and proximal muscles. Transient weakness may occur after sustained myotonia. Mild fixed distal weakness may develop. MC is not associated with systemic features (Figure 2).

Figure 2.

Non-dystrophic myotonias – clinical features and triggers. PMC: paramyotonia congenita; SCM: sodium channel myotonia; MC: myotonia congenita.

Paramyotonia congenita

PMC usually presents in the first decade of life with muscle stiffness predominantly affecting the hands, face and eyelids.⁵ Characteristic features of PMC include worsening of myotonia with cold exposure or continued muscle activity (paradoxical myotonia) and the development of flaccid weakness or paralysis which may persist for hours to days following episodes of myotonia.⁶ Some patients develop permanent weakness over time. Other triggers for myotonia in PMC include potassium-rich food and anaesthetic agents (e.g. succinylcholine). Most affected individuals demonstrate eyelid and grip paramyotonia; however, percussion myotonia is not prominent. Muscle hypertrophy is less common than in MC. PMC is not associated with systemic involvement.

Sodium channel myotonia

SCM is a group of conditions with slightly varying phenotypes characterised by pure myotonia without weakness, which may assist in differentiation of SCM from PMC. Eyelid myotonia is typical in both SCM and PMC. In SCM extraocular muscles, the tongue, hands and legs may also be affected. Myotonia is of variable severity.⁵ Patients may demonstrate warm-up phenomenon (e.g. myotonia fluctuans) or paradoxical worsening with activity (e.g. myotonia permanens). Marked worsening of symptoms may occur with exposure to potassium but patients may be unaffected by exposure to cold.

Diagnosis of myotonias

Percussion is the most sensitive method of detecting myotonia and may be demonstrated by tapping the thenar eminence, forearm extensors or tongue. Myotonia may be elicited by asking the individual to repeatedly grip and relax their hand. Repeatedly opening and closing eyes may demonstrate lid lag and myotonia in PMC and SCM. Myotonia precipitated by exposure to cold is most suggestive of PMC, though may also occur with MC and some types of SCM.

Definitive diagnosis is made by genetic testing. Electromyography is an important test where gene testing is inconclusive. Multiple distal arm and facial muscles should be evaluated. Exercise EMG testing has a sensitivity of 71% in the diagnosis of periodic paralyses and may differentiate between the different types.⁷ The diagnostic value of muscle biopsy is limited. Screening by measurement of creatine kinase may be unhelpful as levels may be normal or minimally elevated in myotonic disorders.

Pregnancy and myotonic disorders

Myotonic dystrophy

DM1 is associated with reduced fertility due to menstrual disturbances, diminished ovarian reserve and poor responsiveness to ovarian stimulation.⁸ In one study, 19.8% with DM1 used in vitro fertilisation (IVF) and 12.1% utilised hormone therapy in their first pregnancy.⁹

Genetic assessment and advice for prospective parents should be offered pre-conception. DM may be diagnosed pre-implantation with IVF. Non-invasive prenatal diagnosis for DM may also be performed using maternal blood or cervical trophoblast cells.¹⁰

DM1 is associated with a high rate of complications in pregnancy, including significantly raised rates of ectopic pregnancy, polyhydramnios (17%–25%), placenta praevia (11%), urinary tract infection (9%), preterm labour (31%–50%), low birth weight (19%) and stillbirth (2.6%) compared with controls.^9,11 Maternal muscle weakness, uterine atony and abnormal placentation may predispose to caesarean section (37%), instrumental delivery (15%), non-vertex presentation (35%) and peripartum haemorrhage (17%). Maternal DM2 is also associated with an increased risk of urinary tract infection (7.6%), preterm labour (50%) and stillbirth (4.6%). There may be a risk of maternal disease progression as a result of pregnancy. Women with DM1 reported increased prevalence of mobility limitations, activity limitations, pain, emotional issues and myotonia during pregnancy and 6 months post-partum compared with 6 months prior to pregnancy.⁹ Similarly, DM2 was associated with a significant increase in the impact of mobility limitations, activity limitations, fatigue, communication difficulties and sleep impairment postpartum compared with pre-pregnancy.

Preconception evaluation should include evaluation of cardiac function, detailed respiratory function testing and assessment for impaired glucose tolerance. Approximately 15% of patients with DM1 and DM2 have left ventricular dysfunction on echocardiography, and 24% have rhythm disturbances due to conduction system fibrosis.^12,13 The effect of pregnancy on cardiac disease in DM is not known. Respiratory complications are common in DM1 as a result of weakness and myotonia of respiratory muscles, pharyngoesophageal weakness and reduction in respiratory drive, potentially leading to alveolar hypoventilation and respiratory failure.

There are no recommendations regarding mode of delivery. The first stage of labour is usually prolonged, and the second stage is often complicated by poor voluntary effort secondary to muscular dysfunction, requiring assisted delivery by vacuum or forceps.

Regional anaesthesia is preferred to general anaesthesia. Use of depolarising muscle relaxants may precipitate a myotonic crisis. Respiratory failure may be precipitated by general anaesthesia. Sugammadex may be useful for the rapid reversal of neuromuscular block induced by non-depolarising neuromuscular blocking agents.¹⁴

As many as 36% of first pregnancies to women with DM1 carried to term result in neonates with congenital DM. As a result of genetic anticipation, even women with mild DM1 may give birth to a severely affected neonate.⁹ Clinical characteristics of pregnancies complicated by congenital DM include high rates of assisted reproductive technology (57%), severe idiopathic polyhydramnios (67%), decreased fetal movements on prenatal ultrasound (37.5%), preterm birth (54%), placental anomalies, postpartum haemorrhage, admission to the neonatal intensive care unit (90%) because of hypotonia and respiratory insufficiency and a high perinatal mortality rate.^15,16 The combination of polyhydramnios and fetal club feet is indicative of congenital DM. The delivery plan for all mothers with DM1 must include preparation for the possibility of the neonate being affected by congenital DM1, with the potential requirement for resuscitation and neonatal intensive care admission.

Myotonia congenita

Symptoms may be aggravated during pregnancy in 25% to 40% of women with MC.¹⁶ Lacomis et al. described a woman with autosomal dominant MC who only developed myotonia and weakness during pregnancy.¹⁷ It was postulated this may occur due to the effect of increased progesterone on intracellular and extracellular potassium concentrations. Another woman developed breathlessness at 39 weeks’ gestation thought to be due to myotonia affecting the respiratory muscles, with resolution of symptoms postpartum.¹⁸ Depolarising muscle relaxants must be avoided as they may precipitate malignant hyperthermia. Myotonic crisis may be precipitated by the physiological stress of labour, volatile agents, painful injections, electrocautery and medications including beta agonists, adrenaline and colchicine. Mexiletene is the drug of choice for women affected by muscle stiffness during pregnancy. Dantrolene should be available during delivery for the management of a myotonic crisis. The patient must be kept warm during labour and postpartum, as must the neonate. Close observation of core temperature and the use of warmed fluids and warming devices should be considered.^19,20 Muscle stiffness may affect positioning of women during vaginal delivery. Regional anaesthesia has been shown to be safe and general anaesthesia should be avoided if possible.²¹ Uterine contractions during labour have been recorded as normal on cardiotocography.²² One case of unexplained intrauterine fetal death has been reported in a woman with MC.

Paramyotonia congenita

Symptoms worsen during pregnancy in 44% of women with sodium channelopathies. Several authors have reported early pregnancy losses associated with cold exposure in women with PMC.²³ Keeping the patient and neonate warm during the peripartum period is essential. Fatal neonatal onset PMC has been reported due to a SCN4A mutation, as well as nine cases of peripheral neonatal hypotonia with impaired suckling/feeding difficulties and respiratory compromise due to PMC mutation.^24,25 Regional anaesthesia is suitable for delivery, though the efficacy of neuroaxial blockade should not be checked with ice as this may precipitate myotonia. Volatile anaesthetic agents may precipitate shivering and paramyotonia. If shivering occurs, small doses of intravenous pethidine or clonidine may be used.⁶ Mexilitene may be used during pregnancy to reduce stiffness with PMC, and acetazolamide and thiazide diuretics may be used as preventive therapy.

Pregnancy planning

A suggested plan for the care of the pregnant woman with a myotonic disorder is summarised in Table 2.

Table 2.

General principles for pregnancy care in myotonic disorders.

Preconception

Precise diagnosis maternal condition

Genetic counselling

Consider preimplantation gene diagnosis if IVF planned

Assess cardiac and respiratory function – echocardiogram, BNP, ECG ± Holter; respiratory function tests including PaCO2

Assess functional status, skeletal deformity, pelvis, airway access and contractures

Bone density if wheelchair dependent

Physiotherapy, OT and speech therapy assessments

HbA1c exclude impaired glucose tolerance

Folic acid; review of medications re safety in pregnancy

During pregnancy

Consider prophylactic low molecular weight heparin if wheelchair bound

Regular respiratory function tests and/or echocardiography if resp/cardiac compromise

MRI spine if skeletal deformity to guide regional anaesthesia

Establish delivery plan – mode of delivery, anaesthesia, postpartum care

Treat gastroesophageal reflux

Regular ultrasound shows growth of fetus, features of congenital DM, polyhydramnios, placenta

Labour and delivery

Presence of multidisciplinary team; availability of dantrolene, antiarrhythmics

Avoid cold, shivering and painful injections – consider warming IV fluids

ECG telemetry during labour and 24 h postpartum if cardiac compromise

Continuous pulse oximetry and transcutaneous pCO2 if respiratory compromise

Caution with MgSO4

Vaginal delivery – early epidural, consider forceps/vacuum, active management third stage

Caesarean section – regional anaesthesia preferable to general; depolarising muscle relaxants contraindicated; greater potential for respiratory depression with other agents

Consider intensive care admission for mother and/or baby postpartum

ECG; electrocardiography; DM: myotonic dystrophy; BNP: brain natriuretic peptide; OT; occupational therapy.

Conclusion

Pregnancy in women with myotonic disorders may be associated with considerable risk for mother and baby. Pre-conception counselling, multidisciplinary team management during pregnancy and careful planning of delivery and postpartum care are paramount.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Ethical approval

Research approval was waived by the Mater Health Human Research Ethics Committee.

Informed consent

The patient described provided written informed consent for publication.

Guarantor

AM is the corresponding author and the guarantor of the present work.

Contributorship

AM researched and wrote the manuscript and cared for the patient described in the case report.