Treatment considerations in myasthenia gravis for the pregnant patient

ABSTRACT

Introduction

Myasthenia gravis (MG) is an autoimmune disease where muscle antibodies form against the acetylcholine receptor (AChR), MuSK, or LRP4 at the neuromuscular junction leading to weakness. Patients worry about consequences for pregnancy, giving birth, nursing, and child outcome.

Areas covered

This review lists the pharmacological treatments for MG in the reproductive age and gives recommendations. Consequences for pregnancy, giving birth, breastfeeding, and child outcome are discussed.

Expert opinion

Pyridostigmine, corticosteroids in low doses, and azathioprine are regarded as safe during pregnancy and should be continued. Mycophenolate mofetil, methotrexate, and cyclophosphamide should not be used in reproductive age. Rituximab should not be given during pregnancy. Other monoclonal IgG antibodies such as eculizumab and efgartigimod should be given only when regarded strictly necessary to avoid long-term and severe incapacity. Intravenous and subcutaneous immunoglobulin and plasma exchange are safe treatments during pregnancy and are recommended for exacerbations with moderate or severe generalized weakness. Most MG women have spontaneous vaginal deliveries. Indications for Cesarean section are obstetrical and similar to non-MG women. Neonatal myasthenia manifests as a transient weakness caused by the mother’s IgG muscle antibodies and affects 10% of the babies. MG women should be supported in their wish to have children.

KEYWORDS:

• Myasthenia gravis
• pregnancy
• thymus
• immunosuppressive drugs
• pyridostigmine
• pharmacotherapy
• neonatal myasthenia

1. Introduction

Myasthenia gravis (MG) is an autoimmune disease where antibodies against the acetylcholine receptor (AChR) in the postsynaptic membrane at the neuromuscular junction cause the typical muscle weakness [1,2]. More rarely, pathogenic antibodies are instead directed against muscle-specific kinase (MuSK) or lipoprotein-related protein 4 (LRP4) antigens functionally linked to AChR in the membrane. The muscle weakness can be generalized or localized. It occurs most frequently in extraocular muscles with diplopia and ptosis as troublesome symptoms. Weakness in swallowing and speech muscles as well as in facial muscles is common. Neck, shoulder, and arm muscles have frequently some weakness, whereas leg muscles are rarely affected [3]. Respiratory muscle weakness represents the major threat of MG, and myasthenic crisis with the need of ventilatory support can occur, especially during respiratory infections. Fluctuations during the day and over time are typical for MG. Repetitive and prolonged muscle use increases or precipitates the weakness.

Immunosuppressive and symptomatic drug treatments represent key therapies for patients with MG. Most patients do well with optimal treatment, being in pharmacological remission or with only minimal symptoms. However, 10–20% of the patients are difficult to treat and continue to have moderate or severe muscle weakness with standard therapies [4]. Even MG patients with minimal symptoms have a reduced quality of life and experience daily-life restrictions, in part because they fear a deterioration of their MG [5].

Women in reproductive age can be affected by MG. For all treatment considerations in this patient group, potential consequences for pregnancy need to be considered. Young females with MG always need information about expected disease development if pregnant, any harmful effects of their therapy for the child, recommended strategies for giving birth and breastfeeding, and how the MG tends to develop after giving birth. Most importantly they want to know about any risks for the baby, both due to heredity, mother’s drug treatment, and transplacental transfer of the pathogenic IgG antibodies. In a German study, one half of the responding MG females reported that they had abstained from having a child or further children because of their disease [6]. With optimal treatment, there should hardly be any MG-related restrictions for the patients having children. Correct, extensive, and repeated information to the patients as well as to their partners is necessary, and also regular follow-ups by specialists in the field. Controlled studies of drug treatment and other interventions in pregnant MG females are lacking.The statements and recommendations in this article are based on a personal evaluation of current evidence including reviews and guidance papers.

2. Epidemiology

MG subgroups are defined according to age at debut, presence of pathogenic autoantibodies, and thymus pathology (Table 1) [3]. Five of these six MG subgroups include women in reproductive age. The total MG prevalence in European women below age 50 years is around 120 per million and with an annual incidence of 5–10 per million [7,8]. One-third of Norwegian MG patients had their first positive AChR antibody test before age 50 years, and this group included two-thirds females and one-third males [9]. Similarly, 40% of all females that used pyridostigmine for MG were below age 50 years [10]. In China and other Far East countries, juvenile MG with debut during childhood is common [11]. Juvenile MG is more common in females than in males [12]. Patients can go into clinical remission, a few even with no further need of MG drug treatment. However, MG patients in remission still have circulating muscle antibodies. A previous MG diagnosis is therefore valid even without present symptoms regarding precautions before and during pregnancy. Thymomas occurs in 10% of all MG patients, but they are rare in females in reproductive age.

Table 1. Subgroups of myasthenia gravis (MG) according to antibody, debut age, and thymus pathology. Females in reproductive age are represented in five of these six subgroups.

Subgroup	Antibody	Debut age	Sex	Thymus
Early onset MG	AChR	< 50 years	Two thirds female	Hyperplasia
Late onset MG	AChR	>50 years	Slightly more males	Atrophy
Thymoma MG	AChR	Any	Equal	Neoplasia
MuSK MG	MuSK	Any	Two thirds female	Normal
LRP4 MG	LRP4	Any	More females	Normal
Seronegative MG	None	Any	Equal	Variable

MuSK MG is a rare disease, constituting less than 5% of all MG cases. In Europe, MuSK MG is more common in south than in north, whereas it is the opposite in China [13]. Females constitute more than 70% of MuSK MG patients [14]. MuSK MG tends to have onset during reproductive age, and with a peak late in the third decade [14,15].

In 15–20% of MG patients, no antibodies against the neuromuscular junction, neither against AChR and MuSK, can be detected by routine assays (seronegative MG). This group is heterogeneous. In one half of such patients, antibodies against AChR or MuSK can be found with more sensitive and cell-based assays [16]. Seronegative MG patients tend to have a mild disease, and among those with ocular symptoms only, nearly one half do not have detectable antibodies in serum [17]. The precautions and recommendations for pregnancy and giving birth do not differ among MG patients with and without detectable muscle antibodies.

3. Pathophysiology

The potential consequences that MG have for pregnancy, giving birth, and the developing child are due to the disorder as an IgG-antibody-mediated disease where the autoantibodies bind to molecules in the postsynaptic membrane at the neuromuscular junction. The antibodies bind either to AChR or to molecules functionally linked to AChR such as MuSK or LRP4. The antibody binding reduces the activity and numbers of the AChR. Increased destruction of AChR through antibody-induced complement activation and AChR cross-linking is the most important [2].

Thymus induces MG in those with a thymoma and in early onset MG with AChR antibodies and thymic hyperplasia [18]. In MuSK MG, thymus has no pathogenic role.

4. Heredity

For family planning, hereditary aspects of a disease are always relevant. MG is not a hereditary disease, and no single genes cause MG. However, MG has a hereditary component. This is in part MG specific, in part due to a genetic disposition for autoimmune disease in general. Genes associated with MG differ according to the various MG subgroups as they have been defined in Table 1.

The concordance MG rate of 35% in monozygotic twins versus 5% in dizygotic twins [19] illustrates the genetic MG component, but at the same time shows that non-genetic environmental factors are important. Among 264 unselected Finnish MG patients, 11 were siblings [20]. Two mothers had a child with MG, and MG occurred in six cousins in this cohort. In a Spanish cohort, 3.5% of the MG patients had a first or second degree relative with MG [21]. A population-based study from Taiwan found that the relative risk for MG was 18 for patient siblings, 6 for parents, and 6 for children [22]. This difference for various types of first-degree relatives illustrates that siblings more than parent–child are exposed to the same environmental factors at critical stages. The absolute MG risk is still very low for the children of an MG mother, around 1%. In counseling before pregnancy, it should be underlined that this lifetime risk is nearly negligible compared to all other health risks that an individual faces. The lifetime risk for an autoimmune disease increases 10–20-fold when a parent has MG [23,24].

HLA-genes contribute most to the genetic MG risk, but genes regulating other immune factors or AChR function influence this risk as well [2]. No gene tests are relevant for MG patients who plan to conceive.

5. Symptomatic pharmacological treatment

Acetylcholine esterase inhibitors are used daily by nearly all MG patients as they improve muscle strength in MG specifically. Pyridostigmine is the favored drug [10]. This drug is regarded as safe in pregnancy and can be continued unchanged when trying to conceive and when becoming pregnant [8,25]. The drug does not cross the placenta in significant amounts. Some women still chose to reduce or stop their pyridostigmine treatment during pregnancy [26]. This may explain an MG exacerbation during pregnancy.

6. Immunosuppressive pharmacological treatment

Most MG women in reproductive age need immunosuppressive drugs for optimal treatment of their disease. A key question is if their drugs have any teratogenic potential. Randomized controlled studies to study teratogenicity are impossible to perform. Animal studies do not give a definite answer for humans. Registry studies including a large and unselected number of pregnancies are helpful, and also long-term clinical observations. A small increase in risk for the child linked specifically to the use of one drug may be difficult to detect, but a marked increase in malformations or any other adverse effects will be identified.

Prednisolone/prednisone and azathioprine are recommended as first-line treatments for MG, and often in combination [1,27,28]. These drugs are in general regarded as safe during pregnancy [8,25,29–32]. For prednisolone and prednisone, the concentration in the fetal circulation is 10% or less of that in the mother [25,33]. An increased occurrence of cleft lip and palate that was reported in previous, large registry studies was most probably due to the disease for which the corticosteroid treatment was given and not caused by prednisolone [23,25]. A large Danish registry-based examination of 51,973 infants exposed to glucocorticoids found no increased risk for such malformations [34]. A recent, retrospective Australian study found no increased risk of cleft palate or neural tube defects in women without autoimmune disease but receiving corticosteroids to avoid implantation failure after in-vitro fertilization (IVF) [35]. However, in that study of 597 births where the mother had used corticosteroids after IVF, there was an increased risk of urogenital congenital anomalies. High-dose corticosteroids may contribute to pregnancy complications such as diabetes and hypertension. In a recent study of 1490 mothers with inflammatory bowel disease, adjusted multivariate analyses found that corticosteroid treatment was associated with preterm birth and neonatal intensive care unit (ICU) admission [36]. Intrauterine growth restriction, preterm birth, and premature rupture of membranes have been reported to occur more frequently with high-dose corticosteroids [33,37,38]. Before conceiving, it should be decided if ongoing corticosteroid treatment is necessary to control the MG. Prednisone and prednisolone should be continued only in the women that need this treatment to control their disease. It is recommended to keep the daily prednisolone dose as low as possible and preferentially below 20 mg. Less than 10% of prednisone and prednisolone is transferred to breast milk [33]. Breastfeeding is recommended with daily doses below 20 mg [37]. With higher doses, breastfeeding should preferentially be adapted to time for corticosteroid intake.

Azathioprine has been used for decades by pregnant women and has a solid basis of data showing compatibility with pregnancy [38]. Any reported differences between patient groups and controls are due to mother’s disease and total disease burden, not azathioprine. A recent meta-analysis of eight studies covering females with inflammatory bowel disease found no increased malformation risk for those on azathioprine [39]. However, this study reported a borderline significant association to preterm birth, with a relative risk of 1.3 [39]. Azathioprine is a prodrug that needs a liver transformation to be active. No active drug enters through placenta to the developing child [33]. Furthermore, the fetal liver is not yet mature for azathioprine metabolization [40].

Mycophenolate mofetil, methotrexate, and cyclophosphamide are immunosuppressive drugs used for MG and that have a teratogenic potential [25,29,41]. These drugs should therefore be avoided in all MG women with a potential for becoming pregnant (aged 16–50 years). These drugs should be terminated more than 3 months before conception. However, this is not a sufficient precaution as a large proportion of pregnancies are not planned. Cyclosporine is regarded as safe regarding long-term child development [42]. A recent meta-analyses mainly included pregnant women that used cyclosporine for previous organ transplantation [43]. The increased risk for preeclampsia, preterm delivery, and low birth weight can most probably be attributed to their underlying condition. Hypertension is a side-effect of cyclosporine and unwanted in pregnancy.

Rituximab is a monoclonal IgG antibody against the CD20 antigen on B lymphocytes. The drug is widely used in the treatment of MG [2,44–46]. One half of MG patients respond. The manufacturer does not recommend use during pregnancy nor during 12 months before pregnancy. Consensus-based treatment guidelines and recommendations reduce this period to 3 months before pregnancy or state that the drug can be continued through conception [37,47]. Rituximab has an elimination half-life of about 3 weeks. Drugs are considered to have fully cleared after five half-lives, that is, 4 months for rituximab [47] IgG antibodies pass placenta. However, until week 13 of the pregnancy the IgG concentrations in the fetus are very low, and even at week 17–22 it is only 5–10% of the maternal level [48]. Rituximab treatment during pregnancy can lead to transient B-cell depletion in the newborn baby and is therefore not recommended. However, in some patients with severe and difficult-to-treat MG, the risks of the disease and alternative treatments may outweigh the very low risks of continued rituximab treatment in pregnancy.

The C5 complement inhibitor eculizumab improves the muscle weakness in MG [49]. Eculizumab is an IgG antibody, and the kinetics during pregnancy are similar to other IgG monoclonal antibodies. Available data indicate that eculizumab treatment during pregnancy has no adverse effects on complement activity in the newborn [50]. Exposure to eculizumab during pregnancy did not seem to infer any increased risks for 434 women and their babies [51]. The manufacturer states that eculizumab can be given during pregnancy when regarded strictly necessary.

Efgartigimod is a human antibody IgG1 fragment that blocks FcRn receptors, inhibits recycling of IgG, and thereby reduces the concentration of all IgG antibodies including the pathogenic antibodies in MG. This improves the MG muscle weakness [52]. There are no data on the use of efgartigimod during pregnancy. It will reduce the IgG concentration in the child and thus may reduce the passive protection against infections during the first weeks after birth. On the other hand, it may also reduce the risk of neonatal myasthenia in the newborns. FcRn blockers may represent a prophylactic therapy for disorders mediated by transplacental IgG antibody transfer from mother to child.

Intravenous immunoglobulin (IvIg) and plasma exchange represent effective treatments for MG exacerbations and MG crisis [1]. In selected patients these treatments are also used for maintenance. Both treatments are safe during pregnancy. IvIg in particular is used for MG exacerbations during a pregnancy. The therapeutic effect lasts for about 3 months. IvIg and plasma exchange represent the preferred treatments of pregnant MG women with a proven risk of severe neonatal myasthenia, arthrogryposis, fetal AChR inactivation syndrome, or MG-related miscarriages [23,25]. Subcutaneous immunoglobulin is effective in mild-to-moderate exacerbations of MG [53] and is equally safe in pregnancy. Antigen-specific immunoabsorption, removing only the antibodies against AChR or MuSK, is a modification of plasmapheresis and is clinically effective but not more effective than ordinary plasmapheresis [54].

7. Thymectomy

Thymectomy with removal of all thymus tissue represents a recommended primary treatment for generalized MG with AChR antibodies in females at reproductive age [27,55]. Thymectomy early after MG debut gives better results than postponing the operation [56]. However, due to complication risks, thymectomy is not recommended during pregnancy [30]. MG women who have undergone thymectomy have less risk for MG exacerbations during pregnancy, and they have also less risk for giving birth to babies with neonatal myasthenia [57]. Thymectomy is therefore recommended in MG women with AChR antibodies prior to pregnancy.

8. Pregnancy outcome

MG does not influence fertility. However, in MG, there is an increased risk for all autoimmune comorbidities and some may have such a consequence [8]. Most MG treatments do not influence fertility. Cyclophosphamide is rarely used in MG, but this drug can reduce female fertility [58]. A large proportion of MG women reported that they had abstained from pregnancy or had fewer children than they would have wanted because of their MG [6]. The most common cause for abstaining from children was fear of adverse MG drug effects on the child.

MG pregnancies should preferentially be planned to a phase where the MG is stable. The treating neurologist and the obstetrical services should cooperate and communicate throughout the pregnancy [30]. Folic acid supplement is recommended before conception and during pregnancy for MG women in the same way as with no MG [8,59].

Pregnancy is usually uncomplicated in MG. Most complications occur at the same frequency with and without MG [60,61]. Preterm rupture of amniotic membranes occurs with a near doubled frequency in MG patients versus controls, 6.7% compared to around 3% in the general population [62,63]. The reason for this is not known. Preeclampsia and eclampsia risks do not differ.

A registry-based, nationwide cohort study from Denmark did not find any increased frequency of pregnancy loss in MG [64]. Pregnancy loss was defined as miscarriage, blighted ovum, or missed abortion. This occurred in 59 out of 463 MG pregnancies. They listed six events with two or more pregnancy losses; also this frequency is similar to the non-MG group. Case-series from France, Italy, Turkey, and Brazil reported all together 26 miscarriages in 162 pregnancies, i.e. 16% [8]. This is similar to the general population. In a US cohort of azathioprine users in the first pregnancy trimester for either autoimmune disease or after transplantation, spontaneous abortions occurred in 105 out of 471 pregnancies, i.e. 22%, and another 8 were stillbirths [65]. That was markedly lower figures than for mycophenolate mofetil, a drug with a well-known teratogenic risk.

Pregnancy, puerperium, and lactation can all influence the course of MG. This is for a large part due to hormonal changes [66]. However, the risk for MG onset did not change during pregnancy in a population-based Norwegian and Dutch MG cohort of 246 women [67]. In contrast, the risk for MG debut was five-fold increased during the first 6 months after giving birth. The risk was somewhat higher after the first child than after later births. Hormonal, immunological, and stress mechanisms all contribute to the increased puerperal risk. This risk is not MG specific but is seen for most autoimmune disorders.

Pregnancy can influence manifest autoimmune diseases including MG. Provided that their MG is under good control before pregnancy, the majority of women can be reassured that they will remain stable throughout pregnancy [30]. If worsening occurs, it is more likely during the first few months. In a recent, systematic review, Su et al. identified 15 MG cohorts, 734 pregnancies, and 574 MG women [68]. Their meta-analysis revealed an estimated proportion of 0.36 for MG worsening and of 0.28 for MG improvement during and shortly after pregnancy. A slightly elevated worsening proportion occurred during the third trimester. Thymectomy before pregnancy was a determinant for an improved MG outcome. Another review stated that 19–50% of pregnant MG women experienced a worsening, 30–59% remained stable and about 20% improved [57]. The article found that most MG exacerbations occurred in the first and second trimesters and after delivery. Exacerbations during pregnancy are usually mild to moderate, and myasthenic crisis during pregnancy is rare [8,57]. The cohort studies have failed to find consistent risk factors for MG worsening during pregnancy. Neither clinical nor immunological markers have been identified. Severe MG tends to be more severe also during the pregnancy. Outcome for mother’s MG in one pregnancy does not predict MG outcome in the next ones [8]. Taken together, these observations indicate that pregnancy in itself does not represent a main influencing factor on mother’s MG, but rather that non-pregnancy factors are more important for changes in MG symptom severity also during a pregnancy. Pregnancy and puerperium did not influence MG severity in 27 pregnancies where the mother had MuSK antibodies [69]. Treatment of MG crisis and severe exacerbations is similar to non-pregnant patients and includes respiratory support, IvIg, or plasma exchange, treating any precipitating factors, and intensified immunosuppression.

9. Giving birth

MG women should always give birth at hospitals with experience in treating newborn children with respiratory support because of the risk of neonatal myasthenia. Spontaneous vaginal delivery should be the objective and should be actively encouraged [25,30]. However, cohort studies tend to show a higher frequency of Cesarean section in MG females, especially for planned sections. Figures for emergency Cesarean sections are either slightly elevated or similar to non-MG women. Absolute rates for Cesarean sections vary very much between countries, but the MG – non-MG difference is similar [8]. More than 50 countries in the world have Cesarean section rates above 27% for the total population [70].

Norwegian registry-based data up till the year 2001 showed that 17% (MG) versus 8.6% (non-MG) had Cesarean section [26]. Unpublished data for the years 1999–2018 showed that these figures had increased to 20% and 15%, respectively. Emergency Cesarean sections constituted 46% for MG and 62% for non-MG of the totals. Frequency of emergency Cesarean section and of instrumentally assisted vaginal births (vacuum or forceps) did not differ in MG and non-MG women. Cesarean section in MG should be performed for obstetric indications [25,57]. These include prolonged labor and an exhausted mother. MG mothers may reach exhaustion before those without MG. In severe or moderate generalized MG, IvIg treatment or plasma exchange is sometimes undertaken toward the end of the pregnancy to improve muscle strength before giving birth and in the puerperium.

10. Outcome for the child

Neonatal myasthenia is transient and occurs in 5–15% of all babies born to mothers with MG [8,62,71,72]. The frequency differs between reported cohorts, most probably because of variation in sensitivity for detection and diagnosis. Typical symptoms are poor sucking due to reduced muscle strength, dysphagia, a weak cry, and sometimes also general hypotonia. Insufficient respiration, aspiration, and pneumonia represent rare and severe symptoms. The symptoms appear during the first 3–4 days after birth. They typically last for a few weeks, often only for some days. The weakness improves gradually and does not last longer than 3 months.

Neonatal myasthenia is caused by mother’s IgG antibodies against antigens in the postsynaptic muscle membrane. These antibodies are actively transported across placenta during the pregnancy. They bind to their respective antigens in the child and can cause muscle weakness as long as they persist. Properties of the child’s AChR combined with the epitope specificities for mother’s AChR antibodies seem to be the most important determinants for neonatal myasthenia. Cross-placental IgG transport does not differ between those with and without neonatal myasthenia [71]. MG mothers with one child with neonatal myasthenia have an increased risk for neonatal myasthenia in all their future children. The risk shows no relation to MG severity in the mother. The condition has been reported for AChR-, MuSK-, and LRP4-MG, and also in MG mothers with no detectable antibodies. Most MG patients without muscle antibodies in standard commercial tests still have such antibodies with more sensitive testing [73].

We examined all MG births in Norway 1967–2000 and found that 5/125 children had definite neonatal myasthenia, whereas another 10 also were transferred to the neonatal ward [26]. For 1999–2018, the neonatal myasthenia frequency was 5%, and in addition 23% were transferred to a neonatal ward, compared to a total of 10% for non-MG mothers (unpublished). Previous thymectomy reduces the risk for neonatal myasthenia [57,74].

Neonatal monitoring for at least 3 days for any development of muscle weakness is required. Special attention should be paid to sucking, swallowing, and crying, in addition to respiration. Most cases of neonatal myasthenia are so mild that no specific treatment is needed. Very low doses of acetylcholine esterase inhibitor will improve the muscle strength, and pyridostigmine and neostigmine have both been used [25]. Help with breastfeeding and other supportive measures are important. For the very rare severe cases, IvIg or plasma exchange is recommended.

Fetal AChR inactivation syndrome has been reported in very few children of MG mothers, caused by the mothers’ AChR antibodies during fetal life [75,76]. The children have permanent muscle weakness, generalized or localized, no fluctuations, and no muscle antibody production.

Arthrogryposis is another rare condition that can appear in children of MG mothers. The skeletal abnormalities and joint contractures are caused by restricted movements in utero. Mothers’ AChR antibodies bind to the fetal type of AChR with gamma subunits [76]. MG is not a dominating risk factor for arthrogryposis in children [77]. A previous child with arthrogryposis or fetal AChR inactivation syndrome represents a strong risk factor in MG [60,76]. We recommend that all MG women who have given birth to a child with any of these conditions are treated with plasma exchange or IvIg shortly before and during all next pregnancies. If there are any signs of arthrogryposis or reduced fetal movements during the pregnancy at ultrasound or other examinations, plasma exchange or IvIg treatment should be started immediately to reduce the AChR antibody concentration in mother and child.

11. Breastfeeding

Breastfeeding is recommended and should be encouraged in MG [25]. This is true for women with AChR-, MuSK-, and LRP4-antibodies, as well as for those without detectable antibodies. IgG levels in maternal milk are only 2% of that in her serum, and the transferred IgG is partially degraded in the gastrointestinal tract of the child [78]. Breast milk does not represent a source for immunity IgG transfer in humans. Breastfeeding seems to reduce the risk for autoimmune disease later in life for the child [79]. This should be especially important for children who already have a hereditary risk.

Breastfeeding is advised against in MG mothers who use mycophenolate mofetil, methotrexate, and cyclophosphamide [25,29]. Pyridostigmine, corticosteroids in low and moderate doses, azathioprine, tacrolimus, cyclosporine, and their relevant metabolites have very low concentrations in breast milk. Mother’s use of these drugs is not a contraindication for breastfeeding. For rituximab, the concentration is 200–300 times lower in breast milk than in maternal serum [80]. Lactation should therefore be safe. Drug concentrations in breast milk are further reduced if the drug intake is timed optimally in relation to the breastfeeding. This is relevant for MG mothers with high and moderately high corticosteroid doses.

12. Patient involvement

Patients decide, doctors give advice. The active involvement of MG patients in all aspects of treatment improves the treatment result [81]. It is a clear discrepancy between how many MG patients view the risks of pregnancy [6] and scientific data presented in original articles, reviews, and guidelines. The best way to fill this gap is to inform female MG patients in reproductive age repeatedly, precisely, and extensively about all aspects of pregnancy and giving birth. Such patient involvement should continue during the pregnancy and in the puerperium. Active input from female MG patients is necessary in research and clinical improvement projects [82]. Patients often report that female health aspects such as pregnancy are neglected by neurologists.

13. Conclusions

MG is a rare autoantibody-mediated disease resulting in muscle weakness. For most female MG patients in reproductive age, this muscle weakness does not interfere with pregnancy. However, the weakness may have some consequences for nursing of the baby. MG patients often worry about a negative influence of their MG medications on the developing child during pregnancy. Apart from mycophenolate mofetil, methotrexate, and cyclophosphamide, which should be avoided in MG females in reproductive age, there is good evidence that the MG drugs are safe and do not increase the risk for malformations or any delayed child development. Rituximab and other monoclonal antibodies should, if possible, be avoided during the pregnancy. Daily doses of prednisolone and prednisone should optimally be kept below 20 mg.

During a pregnancy, MG severity does not change consistently, and the MG remains stable in most patients. In the weeks after giving birth, some deterioration is common due to hormonal changes and increased stress.

Spontaneous vaginal delivery should be encouraged in MG. Cesarean section should be undertaken for obstetrical reasons as in non-MG women.

Neonatal myasthenia appears in 10% of the babies due to cross-placental transfer of IgG antibodies against AChR, MuSK, or LRP4. Rarely, this muscle weakness can lead to feeding difficulties, aspiration, and insufficient respiration. All MG women should give birth at a hospital with a neonatal ICU. Neonatal myasthenia is a transient condition.

All aspects of pregnancy and giving birth should be discussed repeatedly with MG females in reproductive age. Most can be reassured that they during their pregnancies can continue their treatment unchanged and with no clinically relevant increased risk of complications or exacerbations apart from transient neonatal myasthenia.

14. Expert opinion

MG is a chronic disease with localized or generalized muscle weakness. Females with MG and in reproductive age often worry whether pregnancy is safe and whether the nursing of a child will be too demanding. They need precise information and support before and during pregnancy and after giving birth. The birth rates in all Western countries go down, illustrating the need for support from society, family, and the health-care system.

When females in reproductive age start with their drugs for MG, they should be informed about precautions in pregnancy. This information should be repeated at the ordinary MG controls. Pyridostigmine, prednisolone in low and moderate dose, and azathioprine are all safe treatments. Rituximab and other monoclonal antibodies should usually be stopped 3 months before pregnancy or when the pregnancy is confirmed. IvIg and plasma exchange are safe treatments during pregnancy, are recommended for MG exacerbations, and can be used both to reduce the risk for neonatal myasthenia and to prepare the MG mother for giving birth and the puerperium. Mycophenolate mofetil, methotrexate, and cyclophosphamide have a teratogenic potential and should not be given to MG women in reproductive age.

All MG women should give birth at a hospital with a neonatal ICU because of the risk of neonatal myasthenia that can lead to aspiration and weakness of the respiratory muscles. Firm support in the puerperium is important, as the increased risk for MG deterioration in that phase is in part due to lack of sleep and increased stress.

There are no medical reasons for advising against or restricting the number of pregnancies for the large majority of women with MG. Their pregnancies are usually healthy, their MG usually remains stable, they can have ordinary vaginal deliveries, and their children are healthy, even if some have a transitory and mild neonatal weakness.

Article highlights

• Myasthenia gravis (MG) commonly affects females in reproductive age. Many MG women worry about consequences for pregnancy, giving birth, nursing of a baby, and outcome for the child.

• Drug treatment with pyridostigmine, corticosteroids in low and moderate doses, and azathioprine is safe in MG females during pregnancy. Mycophenolate mofetil, methotrexate, and cyclophosphamide have a teratogenic potential and should not be used by MG women in reproductive age.

• Rituximab is not recommended during pregnancy, but it is safe to try to conceive when on the drug. Eculizumab and efgartigimod should be avoided during pregnancy, and given only when regarded strictly necessary to avoid long-term and severe physical incapacity.

• Intravenous immunoglobulin and plasma exchange are safe treatments during pregnancy, should be used for exacerbations with moderate or severe muscle weakness, and can be used to prepare the mother before giving birth and nursing in the puerperium. Subcutaneous immunoglobulin is expected to have a similar effect.

• Spontaneous vaginal delivery is preferred in most MG women, similar to non-MG births. Indications for Cesarean section are obstetrical.

• Transient neonatal myasthenia in the newborn child is caused by transfer of mother’s muscle antibodies across placenta and is usually mild. Severe and permanent motor or skeletal dysfunction due to mother’s MG antibodies is very rare.

• MG women in reproductive age should be informed about pregnancy and giving birth at the time for MG diagnosis and repeatedly at controls. They should be supported in their wish to have children and receive support from the health-care system, including neurologists, and both during and after pregnancy. Active patient involvement is especially important regarding MG female health.

Declaration of Interest

NE Gilhus has received honoraria from UCB, Argenx, Janssen Pharmaceuticals, Alexion, Roche, Merck and Co, and Immunovant. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This manuscript has not been funded.