A quick review on the management of myasthenia gravis during pregnancy
Angel Roselin. S
Deputy Nursing Superintendent, Kauvery Hospital, Tirunelveli.
Abstract
Myasthenia gravis (MG) is a chronic autoimmune neuromuscular disorder characterized by fluctuating skeletal muscle weakness which can pose unique challenges during pregnancy. The common age group at risk are women in the reproductive age group. Severity determines the possible harmful effects on pregnancy. It is important to prevent the administration of drugs and infections which may worsen the condition.
Successful outcome is achieved by multidisciplinary action care team involving obstetricians, neurologists, anesthetists as well as neonatologists. In this review, we discuss various therapeutic options available for the management of the condition during pregnancy and provide recommendations based on recent evidence-based practice.
Keywords: Myasthenia, pregnancy, muscle-specific kinase (Musk)
Introduction:
Neuromuscular junction (NMJ) disorders that include several dysfunctions that ultimately lead to muscle weakness are genetically. acquirws Globally, approximately 150 to 200 out of every million people have myasthenia gravis. The report suggests that in US, almost 37 out of every 100,000 people have myasthenia gravis.
MG is the most common frequent NMJ disorder with a highly polymorphic clinical presentation manifesting predominantly, as the etymology suggests (“mus” Meaning – muscle, asthenia meaning weakness) , with muscle weakness and fatigue. (1) MG represents the largest group of NMJ disorders and occurs because of the impairment of neuromuscular transmission [2]. Given its pathogenetic mechanism and specific anatomical location, MG has become both a prototype for autoimmune disorders and a model for understanding the synaptic function [3]. It is an autoimmune B-cell mediated disease and correlates with the presence of antibodies directed against the acetylcholine receptor (AChR), muscle-specific kinase (MuSK), lipoprotein-related protein 4 (LRP4), agrin, titin, and ryanodine in the postsynaptic membrane at NMJ [3]. MG patients may be categorized into subtypes to facilitate them and to estimate the prognosis. Subtypes based on the clinical presentation and seropositivity include early-onset MG, late-onset MG, thymoma, MuSK, LRP4, seronegative, and ocular MG [4].
MG is a rare disease. It is estimated that most neurologists might encounter a patient with MG once in 3–4 years and that their practice would not include more than four patients with MG simultaneously [5]. As a result of this paucity of cases and because of the uneven distribution and difficult data collection, it may be problematic to describe clear epidemiological patterns for rare diseases with multifactorial causes such as MG. Nevertheless, certain tendencies have been observed over the last decades. The number of MG patients is growing, and it has more than doubled in the last 20 years. This rise is mostly due to a greater MG incidence in the elderly, probably because of better diagnosis, treatment, and increasing longevity of the population. Environmental and genetic causes have also been explored.
Certain epidemiological features of MG are consistent in most studies but have not been explained yet. One of them is the bimodal age distribution with two peaks of incidence: early-onset MG in the third decade (mostly females) and late-onset MG in the elderly (mostly males) [6]. Another epidemiological riddle is the ethnic discrepancy observed when comparing cohorts with different racial origins. The multitude of clinical presentations, as well as the diverse epidemiological aspects, have led clinicians to believe that MG is most likely the result of different diseases that display one indistinguishable clinical picture. The aim of this review is to synthesize some of the epidemiological data available.
Incidence and prevalence:
Based on 35 studies up to 2007 [1], the incidence rate of MG varied from 1.7 to 21.3, with a global rate of 5.3 per million person-years. The pooled incidence rate after 1976 is approximately twice as great as the one before 1976, which is 6.5 vs. 3.5, respectively [7]. In Table 1, we updated this review to 2019, adding 29 studies with a range of 0.15 to 61.33 per million person-years. The global incidence rate of acetylcholine receptor antibody-positive MG ranges between 4 and 18 per million person-years [8]. The incidence of MuSK MG is estimated at 0.1 per million person-years in Holland and 0.32 per million person-years in Greece [1].
Data on MG incidence has varied over time and among different geographical regions, questioning whether there is a real geographical variation (that could point to the disease’s etiology) or if this is due to methodological biases. Most epidemiological studies regarding rare and heterogeneous diseases such as MG bear limitations like small study populations, different inclusion criteria and sources of data, disparate diagnosis criteria, and often provide data that cannot be compared. Nationwide databases, including whole populations, offer a reliable ground for epidemiological studies but are not available in most countries.
The discrepancy in incidence due to methodological biases is expected to disappear as studies expand their year span and their quality enhances, thus possibly revealing real geographical trends.
Depending on the geographic location, the prevalence of MG ranges between 1.5 to 17.9 [1], or between and 2.19 to 36.71 cases/100.000 population (Table 1). This indicates an estimate of 56,000–123,000 patients in Europe [7] and 60.000 in the United States [5].
No epidemiological study has been performed in the Republic of Moldova so far; the only data available come from the neuromuscular division of the Institute of Neurology and Neurosurgery in Chisinau, where 320 patients are being supervised through an MG database, which includes patients diagnosed since 2008. One study determining the prevalence of multiple sclerosis in the Republic of Moldova has been performed [6], laying the ground for further similar epidemiological studies.
Myasthenia gravis: General characteristics pertaining to women
MG affects women twice as often as men. It commonly affects women in second and third decade of life like during the childbearing age. The clinical severity of MG ranges from pure ocular muscle involvement (ocular MG) to generalized muscular weakness (Generalized MG). Generalized MG is further graded mild, moderate and severe depending on degree of weakness. Approximately 80% – 90% of generalized MG patients and 50%-70% of ocular MF patients have AchR antibodies in their serum. Other antibodies which are commonly seen in myasthenic patients include (9) anti-MuSK (muscle-specific kinase) antibodies (seen in about 40% of AchR antibody negative MG patients and (2) antibodies against lipoprotein receptor related protein. Approximately 10% of patients with MG have thymoma. (8,9,10).
Effects of myasthenia gravis on pregnancy and vice versa
As MG commonly affects women of childbearing age, it is not uncommon to encounter a pregnancy complicated by MG. The effects of pregnancy on the severity of MG are variable. In one study, while 30% of patients did not show any change in the status of MG, 29% reported improvement and 41% reported worsening of myasthenic symptoms during pregnancy.[5] Worsening of myasthenic symptoms was usually seen during 1st trimester and in 1st month following delivery while the improvement of myasthenic symptoms was reported during 2nd and 3rd trimesters likely related to pregnancy-induced immunosuppression which occurs during these trimesters.[4,5,6]
The main causes of exacerbations of MG during pregnancy include: (a) hypoventilation due to weakness of respiratory muscles and elevation of diaphragm during pregnancy, (b) puerperal infections, (c) drugs, as well as (d) stress of labor and delivery. A factor which may be predictive of maternal mortality due to MG itself is the duration of MG before index pregnancy. In one study, the risk of maternal mortality was highest during the 1st year after diagnosis of MG and minimal 7 years after diagnosis of MG. However, in general, long-term outcome of MG is not reported to be altered by pregnancy.[14] Furthermore, clinical severity of MG at onset of pregnancy does not predict its course during pregnancy and behavior of MG during index pregnancy does not predict its course during future pregnancies.[13]
In general, MG does not affect pregnancy to a large extent. There is no increased risk of low birth weight, spontaneous abortion or prematurity, although an increased risk of premature rupture of membranes does exist in myasthenic women, reason of which is not very clear. [11,12]
Management issues
Its crucial to have a multidisciplinary team approach comprising of obstetrician, neonatologist/pediatrician and neurologist with active contribution by the patient and her relatives.
Prenatal counseling
Women suffering with MG are planning should be counseled about the possible side effects and treatment option available. As far as possible, women should be involved actively in treatment decisions. Family counseling should include possible complication of the fetus, treatment option, benefits of limiting medication usage, delivery option, medication and their side effects on both mother & fetus. The nature of treatment regimen chosen guided by the severity of MG with special attention to bulbar or respiratory symptoms.
A very important issue which is pertinent to the treatment of MG in women is the timing of thymectomy. Approximately 10% of MG patients have thymoma while 60%–80% have thymic hyperplasia. [2,8] Thymectomy is a standard treatment option for myasthenic patients who have thymic hyperplasia or thymoma. It improves clinical outcomes in MG over a 3-year period. The chances of exacerbations of MG during pregnancy as well chances of neonatal MG are lower in women who have undergone thymectomy as compared to women who did not undergo this procedure. However, there is a lag before therapeutic effects of thymectomy become appreciable.[15] In addition, thymectomy is a major surgical procedure with obvious adverse implications if performed during pregnancy. Thus, young women with MG who are planned for thymectomy should undergo it at the earliest if they are not contemplating pregnancy. If they are pregnant, they should be advised to postpone thymectomy till delivery, if possible. [11,14]
Consideration of pre/intra & post-delivery care:
| Antenatal Care | Intranatal Care | Postnatal care |
|---|---|---|
| Education on importance of antenatal checkup & follow up | Vaginal delivery is safe in MG and should be encouraged. | Maternal AchR antibodies can cross placenta and induce transient muscle weakness in 10%–20% of neonates born to myasthenic mothers. |
| Monitoring on the medication prescribed and their side effects. | First stage doesn’t affect in MG | Thus, all infants born to women with MG should be observed carefully for any signs of muscle weakness including bulbar and respiratory muscles. Although reported to reverse within 3 weeks, this syndrome has been reported to last for as long as 4 months |
| Women with clinical remission can be followed less frequently. | Second stage requires the use of striated muscle; the patient may get exhausted during this stage and may require forceps or vacuum extraction. | Treatment usually includes administration of cholinesterase inhibitor drugs. Rarely ventilator support or even small volume plasma exchange may be required. |
| Symptomatic women should be monitored every 2 weeks during the first two trimester and once every week during 3rd trimester. | Narcotic and neuromuscular blocking agents, sedatives and opioids should be avoided. | |
| Epidural analgesics should be used to relieve pain. | Other complications which are rarely reported in infants born to myasthenic mothers include pulmonary aplasia and arthrogryposis multiple congenita (AMC). The former results from lack of diaphragmatic movements (required for normal lung maturation) due to passive transfer of AchR antibodies to neonates while the later results due to decreased limb movements again due to passive transfer of maternal AchR antibodies to neonates | |
| Women should be advised to count fetal movements and report immediately to the hospital in the case of decreased fetal movement. | Women who are on chronic low dose steroids may be given stress dose of hydrocortisone during intrapartum period. If required cholinesterase inhibitors can be used parenterally (preferably neostigmine). | Polyhydramnios may result in mother due to impaired fetal swallowing. All the pregnant women with MG (even those without clinically significant MG) should be counseled against the possibility of these two complications. Transient hyperbilirubinemia is another complication that may occur in neonates born to myasthenic mothers likely related to use of prednisone and pyridostigmine during pregnancy |
| The timing and frequency of ultrasonography (USG) for fetal well-being is again dictated by clinical status of mother and chances of teratogenicity which is dictated by nature of drugs being administered for MG. | In preeclamptic and eclamptic women use of magnesium sulfate should be avoided as it can interfere with neuromuscular transmission by blocking release of acetylcholine. Methyldopa and hydralazine are drugs of choice for treating severe hypertension in pregnancy. | Breast feeding: |
| Corticoids and anticholinesterase inhibitors are relatively safe in breastfeeding. On the other hand, other drugs such as azathioprine, mycophenolate, cyclosporine, and cyclophosphamide are excreted in breast milk and breastfeeding should be avoided in patients taking these drugs | ||
| In general, USG is carried out frequently in pregnant women with MG to look for fetal well-being and hydramnios. USG is performed even more frequently during MG exacerbations to look for any signs of fetal hypoxia. | ||
| Women should also be screened frequently for asymptomatic bacteriuria, and any infection should be treated promptly as it might worsen MG. | ||
| Frequent assessment of motor, respiratory and cardiovascular systems as well as it is mandatory to do thyroid function test. | ||
| A complete medication history should be included in family counselling |
| S.no | Key Notes about Management of Myasthenia in Pregnancy |
|---|---|
| 1 | The clinical course of MG in pregnancy is variable with approximately equal chances of clinical remission, worsening or remaining status quo. Maximum worsening occurs during 1st trimester and postpartum period. Longer duration of MG before pregnancy lowers the risk of worsening. |
| 2 | MG usually does not affect the course of pregnancy. |
| 3 | Thymectomy, if planned, should be done before conception. |
| 4 | Preconception counseling should be offered to all women with MG. |
| 5 | All women should have frequent antenatal checkups. A list of all drugs that worsen MG should be provided. |
| 6 | Treatment should be individualized. Mild ocular weakness may need only anticholinesterase drugs. More severe MG often needs immunosuppression. Steroids are the drugs of choice (lowest effective dose). Azathioprine/cyclosporine may be used if steroids are not tolerated or ineffective. |
| 7 | Vaginal delivery should be attempted in all women with MG. Cesarean section only for obstetric indications. First stage of labor is usually unaffected. Second stage may need assistance if maternal exhaustion occurs. |
| 8 | Nondepolarizing muscle relaxants, magnesium, and sedatives should be avoided during labor. Regional anesthesia may be used if vaginal delivery is planned. |
| 9 | All newborns of MG mothers should be observed for at least 72 hours due to risk of transient neonatal MG (occurs in 10–20%). |
