179th ENMC international workshop: Pregnancy in women with neuromuscular disorders: 5–7 November 2010, Naarden, The Netherlands

Abstract

Sixteen doctors and scientists met in Naarden, The Netherlands, from 5 to 7 November 2010 to review current knowledge in the field of pregnancy in women with neuromuscular disease. The group was joined by three patients and their families. Participants were from eight countries, namely Belgium, Finland, France, Germany, Italy, Norway, The Netherlands and the United Kingdom. A variety of disciplines were represented, including neurology, clinical genetics, cardiology, respiratory medicine, obstetrics and gynaecology, epidemiology, ethics, a nurse specialist, and a representative from the ENMC research committee. Parenthood is a highly desirable aim in life for many couples, and increasingly this also applies to women affected by neuromuscular disorders (NMDs). Little is known about the effect of individual NMD on the course of pregnancy and delivery and conversely the effect of pregnancy on muscles themselves [[1]Argov Z. de Visser M. What we do not know about pregnancy in hereditary neuromuscular disorders.Neuromuscul Disord. 2009; 19: 675-679Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar]. In the past, many patients have been discouraged from undertaking pregnancy for a variety of reasons. The overarching aim of the workshop was to harness knowledge about pregnancy in NMD with the intention of improving maternal and fetal outcomes. The workshop was structured to first review existing knowledge in the field, and second to propose practical recommendations for each stage of pregnancy, both in general terms and also specific to individual or groups of conditions, for use by all the specialists involved in a woman’s care. The third aim was to stimulate research and collaborative studies in this area. Mandish Dhanjal, UK, gave an overview of physiological changes during normal pregnancy. These include (a) haematological effects such as a dilutional anaemia, reduction in total plasma proteins and an increased thromboembolic risk due to increased clotting (and venous stasis), (b) cardiological changes such as a rise in heart rate, stroke volume and thus a rise in cardiac output by 50%, (c) respiratory changes including a rise in tidal volume and oxygen consumption, (d) immunological changes with infections being more common and (e) musculoskeletal alterations with collagen softening in ligaments and joints and smooth muscle in the gut and uterus undergoing relaxation but with no significant changes in skeletal muscles. As a general rule, women with a vital capacity of under a litre are advised against pregnancy. An important risk relevant to women with respiratory disease is that where maternal hypoxia results in oxygen saturations less than 85%, the livebirth rate is only 12%. Fiona Norwood, UK, presented data on the prevalence of the most common genetic conditions involving muscle, derived from a study of a clinic population in northern England [[2]Norwood F. Harling C. Chinnery P.F. Eagle M. Bushby K. Straub V. Prevalence of genetic muscle disease in Northern England: in-depth analysis of a muscle clinic population.Brain. 2009; 132: 3175-3186Crossref PubMed Scopus (332) Google Scholar]. Five major diagnostic categories accounted for two-thirds of patients, namely the myotonic dystrophies (DM1, DM2), dystrophinopathies (DMD, BMD), facioscapulohumeral muscular dystrophy (FSHD), spinal muscular atrophy (SMA) and limb girdle muscular dystrophies (LGMDs). Hereditary motor and sensory/Charcot-Marie-Tooth (CMT) neuropathies and mitochondrial myopathies were excluded from the study but are also relatively common. Clinical features of the most common disorders were presented. In summary, there is a wide range of physical abilities at child-bearing age, the involvement of cardiorespiratory systems is of paramount importance and knowledge of the precise diagnosis allows a tailored care plan before, during and after pregnancy. Marianne de Visser, The Netherlands, discussed metabolic muscle disorders of glycogen and lipid metabolism. She focussed on Pompe disease which has a prevalence of about 1 in 50.000 in Holland and where the late onset form typically presents as a progressive proximal myopathy with respiratory involvement [[3]Van der Ploeg A.T. Reuser A.J. Pompe’s disease.Lancet. 2008; 327: 1342-1353Abstract Full Text Full Text PDF Scopus (470) Google Scholar]. Anecdotal accounts suggest an exacerbation of weakness associated with delivery. In a larger study of patients with McArdle’s disease, no adverse effects of pregnancy and delivery were documented [[4]Quinlivan R. Buckley J. James M. McArdle disease: a clinical review.J Neurol Neurosurg Psychiatry. 2009; (195040 Published Online First: 22 September 2010)Google Scholar]. In disorders of lipid metabolism, in carnitine palmitoyl transferase deficiency type 2 (CPT2) as an example, patients are unable to derive energy from fatty acid oxidation and so an infusion of glucose is recommended during labour and postpartum [[5]Slater P.M. Grivell R. Cyna A.M. Labour management of a woman with carnitine palmitoyl transferase type 2 deficiency.Anaesth Intensive Care. 2009; 37: 305-308PubMed Google Scholar]. Early neuraxial labour analgesia is recommended to control release of endogenous catecholamines which could precipitate rhabdomyolysis. In VLCAD deficiency, rhabdomyolysis can be triggered by prolonged exercise or fasting, so similar precautions may be needed [[6]Laforet P. Acquaviva-Bourdain C. Rigal O. et al.Diagnostic assessment and long-term follow-up of 13 patients with very long-chain acyl-coenzyme A dehydrogenase (VLCAD) deficiency.Neuromuscul Disord. 2009; 19: 324-329Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar]. Despite the increasing awareness of mitochondrial disease, until now there is very little information about pregnancies in this clinically and genetically heterogenous group. A few case reports of patients with ventilatory failure who had a favourable outcome of pregnancy were published [7Diaz-Lobato S. Gomez Mendieta M.A. Moreno Garcia M.S. Mayorales-Alises S. Arpa Gutierrez F.J. Two full-term pregnancies in a patient with mitochondrial myopathy and chronic ventilatory insufficiency.Respiration. 2005; 72: 654-656PubMed Google Scholar, 8Yuan N. El-Sayed Y.Y. Ruoss S.J. Riley E. Enns G.M. Robinson T.E. Successful pregnancy and caesarean delivery via noninvasive ventilation in mitochondrial myopathy.J Perinatol. 2009; 29: 166-167Crossref PubMed Scopus (12) Google Scholar]. Fiona Norwood, UK, presented a summary of the pathophysiology of myasthenia gravis and the effect of pregnancy on autoimmune diseases. She reviewed relevant studies from the literature, concentrating on seven studies published between 1991 and 2010. Comparison across the studies was difficult due to variation in parameters used, but broadly there was agreement that myasthenic mothers were at higher risk of relapse during and after pregnancy. Immunosuppressive and immunomodulatory treatment also varied across countries, especially the use and timing of thymectomy. Obstetric risks were unclear, with earlier studies suggesting higher interventions were required [[9]Hoff J.M. Daltveit A.K. Gilhus N.E. Myasthenia gravis. Consequences for pregnancy, delivery and the newborn.Neurology. 2003; 61: 1362-1366Crossref PubMed Scopus (106) Google Scholar] but this was not borne out in a later study [[10]Wen J.C. Liu T.C. Chen Y.H. Chen S.F. Lin H.C. Tsai W.C. No increased risk of adverse pregnancy outcomes for women with myasthenia gravis: a nationwide population-based study.Eur J Neurol. 2009; 16: 889-894Crossref PubMed Scopus (37) Google Scholar]. The risk of neonatal myasthenia varied widely among studies, from 9% [[11]Batocchi A.P. Majolini L. Evoli A. Lino M.M. Minisci C. Tonali P. Course and treatment of myasthenia gravis during pregnancy.Neurology. 1999; 52: 447-452Crossref PubMed Google Scholar] to 27% for mothers who had not had a thymectomy [[12]Hoff J.M. Daltveit A.K. Gilhus N.E. Myasthenia gravis in pregnancy and birth: identifying risk factors, optimising care.Eur J Neurol. 2007; 14: 38-43Crossref PubMed Scopus (99) Google Scholar]. There was also discussion about which drugs are safe to use during pregnancy and breastfeeding, and the place and timing of thymectomy. Sabine Rudnik-Schöneborn, Germany, introduced two German patients and summarised their experiences with pregnancy. The first patient has a form of LGMD and found that she became weaker from the 6th month of gestation with no subsequent recovery. The second patient was affected by SMA type II and had an uneventful pregnancy with stable motor and lung function [[13]Rudnik-Schöneborn S. Breuer C. Zerres K. Stable motor and lung function throughout pregnancy in a patient with infantile spinal muscular atrophy type II.Neuromuscul Disord. 2002; 12: 137-140Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar]. A Dutch patient with SMA type II was introduced by Lieve Page-Christiaens, The Netherlands, and presented a powerful firsthand account of the preparation for her pregnancy and delivery. The German woman with SMA II reviewed the psychosocial issues of disabled people becoming parents. She pointed out that there is more structural and social support required to ensure a maximum of self-determination and responsibility independent from income or financial background. In her view it is important to plan a pregnancy at an early stage and to gather as much information as possible from various disciplines. Disabled parents require financial and personal support but they often have to fight hard for their rights. Many affected persons are not aware of their options and sources of support. From the patient’s experience, practical considerations for women using wheelchairs who contemplate a pregnancy include:1.Barrier free home.2.Personal assistance for your own needs to maintain a personal reserve.3.Early integration of help into the household.4.Devices for baby care, e.g. a cot adjustable for height, baby changing unit accessible with a wheelchair, baby carriers.5.Parental assistance in the first years, spouse at home solutions.6.Midwives attendance during and after pregnancy, courses for birth preparation.7.Home visits by the family doctor or pediatrician according to the degree of disability.8.Assistance during hospital stays, in Germany possible with a new law regulating paid assistance by personal employment.9.Early acquaintance of suitable nursery and toddler groups.10.Support to increase self-respect and self-assertion.11.Maintain close relationships to individuals who are familiar with your needs.12.Positive mentality and trust in your abilities. Lieve Page-Christiaens, The Netherlands, addressed important NMDs for which the literature data are available regarding pregnancy: DM1, DM2, SMA, CMT neuropathy, DMD and BMD carriers, FSHD and limb girdle muscular dystrophy (LGMD). She emphasised the process of decision making when contemplating pregnancy. This should start with the alternatives in the preconception planning phase, in particular, when the life span of the mother is reduced, the risk of a pregnancy is high or genetic risks are considered unacceptable by the parents. When the patient becomes pregnant, different pregnancy periods have to be considered: the embryonic (miscarriage risk; teratogenicity of medication, prenatal testing) and the fetal period (fetal growth, fetal anatomy). Prenatal diagnosis has to be discussed. At caesarean section regional anesthesia is to be preferred above general anesthesia in all patients with NMD. Contraindications for medications should be checked meticulously in all patients with NMD, e.g. nitrofurantoine is contraindicated in CMT neuropathy, volatile agents, suxamethonium and drugs inducing rhabdomyolysis are to be avoided in LGMD, DMD and BMD carriers. Karim Wahbi, France, summarised the main cardiac manifestations and their treatment in NMDs. The main diseases at risk for cardiac dysfunction and arrhythmias are Emery–Dreifuss muscular dystrophy, desminopathy, myotonic dystrophy and mitochondrial diseases. The main limiting factor for pregnancy is cardiac systolic dysfunction, as haemodynamic changes during pregnancy, mainly the increase of cardiac output, can lead to decompensated heart failure [[14]Siu S.C. Sermer M. Colman J.M. et al.Cardiac disease in pregnancy (CARPREG) investigators. Prospective multicenter study of pregnancy outcomes in women with heart disease.Circulation. 2001; 104: 515-521Crossref PubMed Scopus (951) Google Scholar]. The removal of cardiac dysfunction treatments such as ACE inhibitors, in order to avoid fetal toxicity, may also contribute to cardiac deterioration. The third trimester, labour and delivery are the periods with the highest risk of cardiac complications. Generally speaking, an ECG and echocardiogram is recommended in all patients at risk for cardiac disease. If the left ventricular ejection fraction (LVEF) is below 45% or a class III–IV NYHA heart failure is present, it might be advisable to discourage pregnancy due to an extremely risk of death, pulmonary oedema, and stroke [[15]Grewal J. Siu S.C. Ross H.J. et al.Pregnancy outcomes in women with dilated cardiomyopathy.J Am Coll Cardiol. 2009; 55: 45-52Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar]. Milder ventricular dysfunction with LVEF between 45 and 60% is also at risk and requires close follow up. In women with cardiac disease an operative delivery may be preferred to avoid the physical stress of labour [[16]Task force on the management of cardiovascular diseases during pregnancy of the European society of cardiologyExpert consensus document on management of cardiovascular diseases during pregnancy.Eur Heart J. 2003; 24: 761-781Crossref PubMed Scopus (346) Google Scholar]. The risk of arrhythmias is also increased during pregnancy and betablockers are the first choice for treatment. In case of sustained tachycardia, electrocardioversion can be applied safely in pregnancy [[17]Ferrero S. Colombo B.M. Ragni N. Maternal arrhythmias during pregnancy.Arch Gynecol Obstet. 2004; 269: 244-253Crossref PubMed Scopus (47) Google Scholar]. Catharina Faber, The Netherlands, gave an overview about the obstetric risks in DM1 which are specifically high when the fetus is affected. The combination of fetal clubfeet and polyhydramnios is indicative of congenital DM1 in the fetus and associated with a high risk of blood loss in the mother at delivery. The condition is complex in its multiorgan involvement and genetic mechanism of anticipation. Well-known complications are polyhydramnios, preterm delivery, placental anomalies and a high perinatal mortality [[18]Rudnik-Schöneborn S. Zerres K. Outcome in pregnancies complicated by myotonic dystrophy: a study of 31 patients and review of the literature.Eur J Obstet Gyn. 2004; 114: 44-53Abstract Full Text Full Text PDF Scopus (64) Google Scholar]. The risk of a congenitally affected child is high even if the mother’s disease is subclinical [[19]Redman J.B. Fenwick Jr., R.G. Fu Y.H. Pizzuti A. Caskey C.T. Relationship between parental trinucleotide GCTrepeat length and severity of myotonic dystrophy in offspring.JAMA. 1993; 269: 1960-1965Crossref PubMed Scopus (176) Google Scholar]. Maternal complications include respiratory infections, cardiac disease, and the hazards of analgesia and anaesthesia. Brain involvement is often associated with apathy, sleepiness and neglect which can hinder social interaction and medical care. In comparison to DM1, DM2 does not show anticipation and congenitally affected children have not been reported. Age at onset is generally later and mostly beyond the reproductive period, and generally pregnancy and delivery outcome is favourable [[20]Rudnik-Schöneborn S. Schneider-Gold C. Raabe U. Kress W. Zerres K. Schoser B.G.H. Outcome and effect of pregnancy in myotonic dystrophy type 2.Neurology. 2006; 66: 579-580Crossref PubMed Scopus (47) Google Scholar]. However, the risk for prematurity is increased, specifically in symptomatic women with DM2. There is some evidence that pregnancy might trigger the clinical manifestation of DM2. Little is known about pregnancy in the non-dystrophic myotonias [[21]Lacomis D. Gonzales J.T. Giuliani M.J. Fluctuating clinical myotonia and weakness from Thomsen’s disease occurring only during pregnancies.Clin Neurol Neurosurg. 1999; 101: 133-136Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar] subdivided into chloride and sodium channelopathies. While gestational complications have not been reported, there is a risk of deterioration in pregnancy of about 40% in chloride channelopathy and up to 80% in sodium channelopathy [[22]Trip J. Drost G. Ginjaar H.B. et al.Redefining the clinical phenotypes of non-dystrophic myotonic syndromes.J Neurol Neurosurg Psychiatry. 2009; 80: 647-652Crossref PubMed Scopus (71) Google Scholar]. A hormonal influence is likely as many patients experience an influence of menstruation on myotonia. Anne Kjersti Daltveit, Norway, reported the results of the pregnancy outcome in a series of 49 Norwegian patients with known CMT neuropathy at the time these patients entered the national birth registry [[23]Hoff J.M. Gilhus N.E. Daltveit A.K. Pregnancies and deliveries in patients with Charcot-Marie-Tooth disease.Neurology. 2005; 64: 459-462Crossref PubMed Scopus (37) Google Scholar]. In this cohort a higher risk of postpartum bleeding, uterine atony and placental anomalies were found, also an increased rate of abnormal presentation. Operative deliveries were recorded to be twice as frequent in comparison to a control population. On the contrary, no increased pregnancy and delivery complications were found in a series of 21 CMT type 1 patients recruited retrospectively by questionnaires in Germany and Australia [[24]Rudnik-Schöneborn S. Röhrig D. Nicholson G. Zerres K. Pregnancy and delivery in Charcot-Marie-Tooth disease type 1.Neurology. 1993; 43: 2011-2016Crossref PubMed Google Scholar]. In more than one third of patients an exacerbation of CMT disease was reported in at least one pregnancy. As yet there are no genotype-phenotype correlations, and it was agreed that the discrepancy of the results is related to the different ascertainment of data. Further studies are needed to solve this question. Sabine Rudnik-Schöneborn, Germany, gave an overview of published and own data on SMA, LGMD and FSHD pregnancies. In SMA II knowledge of the respiratory situation is essential for pregnancy planning. While successful pregnancies have been reported in women with vital capacities as low as 11% [[25]Flunt D. Andreadis N. Menadue C. Welsh A.W. Clinical commentary: obstetric and respiratory management of pregnancy with severe spinal muscular atrophy.Obstet Gynecol Int. 2009; ([epub 2009, May 19])PubMed Google Scholar], there is an increased risk for miscarriages or stillbirths in patients with poor lung function which is still ill-defined. In SMA II and SMA III there is an increased preterm birth rate and most pregnancies end now via a planned caesarean section [[26]Rudnik-Schöneborn S. Zerres K. Ignatius J. Rietschel M. Pregnancy and spinal muscular atrophy.J Neurol. 1992; 239: 26-30Crossref PubMed Scopus (43) Google Scholar]. However, there is still controversy about the appropriate options for anaesthesia and analgesia management in SMA patients, as information is limited [25Flunt D. Andreadis N. Menadue C. Welsh A.W. Clinical commentary: obstetric and respiratory management of pregnancy with severe spinal muscular atrophy.Obstet Gynecol Int. 2009; ([epub 2009, May 19])PubMed Google Scholar, 27McLoughlin L. Bhagvat P. Anaesthesia for caesarean section in spinal muscular atrophy type III.Int J Obstet Anesth. 2004; 13: 192-195Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar]. Similar conclusions are applicable for the heterogeneous group of muscular dystrophies [28Allen T. Maguire S. Anaesthetic management of a woman with autosomal recessive limb-girdle muscular dystrophy for emergency caesarean section.Int J Obstet Anesth. 2007; 16: 370-374Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar, 29Black C. Said J. Normal vaginal delivery in a patient with autosomal recessive limb-girdle muscular dystrophy.Obstet Med. 2010; 3: 81-82Crossref Google Scholar, 30Molyneux M.K. Anaesthetic management during labour of a manifesting carrier of Duchenne muscular dystrophy.Int J Obstet Anesth. 2005; 14: 58-61Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar] but due to a variable progression – in comparison to stable SMA III – more women report a negative influence of pregnancy on their muscle disease [[31]Rudnik-Schöneborn S. Glauner B. Röhrig D. Zerres K. Obstetric aspects in women with facioscapulohumeral dystrophy, limb-girdle muscular dystrophy and congenital myopathies.Arch Neurol. 1997; 54: 888-894Crossref PubMed Scopus (53) Google Scholar]. The information for FSHD is largely based on a small German and Australian series [[31]Rudnik-Schöneborn S. Glauner B. Röhrig D. Zerres K. Obstetric aspects in women with facioscapulohumeral dystrophy, limb-girdle muscular dystrophy and congenital myopathies.Arch Neurol. 1997; 54: 888-894Crossref PubMed Scopus (53) Google Scholar] and a larger American study [[32]Ciafaloni E. Pressman E.K. Loi A.M. et al.Pregnancy and birth outcomes in women with facioscapulohumeral muscular dystrophy.Neurology. 2006; 67: 1887-1889Crossref PubMed Scopus (35) Google Scholar] which yielded conflicting results as to the incidence of operative deliveries and preterm birth rate. Resolving the discrepancy necessitates further prospective studies. About 20–25% of pregnant women experience persistent worsening of motor function which is in line with what is observed in LGMD and SMA III–IV. Carina Wallgren-Pettersson, Finland, summarised published reports on pregnancy, delivery and anaesthesia for delivery in congenital myopathies. Such reports are scarce, but the overall picture is that while there are a number of medical aspects important to consider, the outcome for mother and child has been favourable [33Eskandar O.S. Eckford S.D. Pregnancy in a patient with nemaline myopathy.Obstet Gynecol. 2007; 109: 501-504Crossref PubMed Scopus (9) Google Scholar, 34Foster R.N. Boothroyd K.P. Caesarean section in a complicated case of central core disease.Anaesthesia. 2008; 63: 544-547Crossref PubMed Scopus (13) Google Scholar, 35Wallgren-Pettersson C. Hiilesmaa V.K. Paatero H. Pregnancy and delivery in congenital nemaline myopathy.Acta Obstet Gynecol Scand. 1995; 74: 659-661Crossref PubMed Scopus (12) Google Scholar]. The most essential clinical consideration is for the respiratory status of the woman affected with a congenital myopathy who is considering pregnancy [[36]Wallgren-Pettersson C. Bushby K. Mellies U. Simonds A. 117th ENMC workshop: ventilatory support in congenital neuromuscular disorders: congenital myopathies, congenital muscular dystrophies, congenital myotonic dystrophy and SMA (II). April 4–6th 2003, Naarden, The Netherlands.Neuromuscul Disord. 2004; 14: 56-69Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar]. Further aspects to assess are cardiac status, scoliosis, contractures including jaw lock, small mouth, neck problems, weakness of abdominal muscles and any smooth muscle weakness. Corrado Angelini, Italy, addressed the question of exacerbation of muscle weakness in different NMDs and the factors that might be related to it. According to his own experience, about two thirds of patients with LGMD and DMD symptomatic carriers show worsening in pregnancy [[37]Angelini C. Limb-girdle muscular dystrophies: heterogeneity of clinical phenotypes and pathogenetic mechanisms.Acta Myol. 2004; 23: 130-136PubMed Google Scholar]. Triggering factors are increasing body weight, metabolic changes and mechanical influences, e.g. diaphragmatic elevation. The depletion of vitamin D stores can aggravate osteoporosis. After delivery muscle weakness may deteriorate due to body temperature elevation, eating disorders, postpartum depression and hormonal changes. Management in pregnancy should include weight control and adequate physical activity. Louise Hastings, UK, stressed the importance of individual support of women with NMD contemplating a pregnancy. Frequent concerns are the possible burden of a disabled mother to a family and the understanding of the social network. Nurse specialists can help to plan a pregnancy, meet the patient at home, arrange meetings with other women with comparable experiences, and can discuss specific problems and needs. Willem Verpoest, Belgium, discussed the possible reproductive options in couples with infertility problems, which is not an issue in most NMDs apart from DM1. He presented data from the long-standing experience with preimplantation genetic diagnosis (PGD) in Belgium. Decision making for PGD includes cognitive appraisal (financial risks, misdiagnosis, success rates and time line), emotional response (pain, physical and psychological burden) and moral judgements regarding the rights and status of the embryo. Data are available for DM1 [[38]De Rademaeker M. Verpoest W. De Rycke M. et al.Preimplantation genetic diagnosis for myotonic dystrophy type 1: upon request to child.Eur J Hum Genet. 2009; 17: 1403-1410Crossref PubMed Scopus (14) Google Scholar], CMT [[39]De Vos A. Sermon K. De Rijcke M. et al.Preimplantation genetic diagnosis for Charcot-Marie-Tooth disease type 1A.Mol Hum Reprod. 2003; 9: 429-435Crossref PubMed Scopus (23) Google Scholar] and FSHD couples, and pregnancy rates were similar around at 20–24% in these disease groups. As for DM1, success rates did not correlate with CTG repeat length but the number of pregnancy complications was higher than in other patient populations [[40]Verpoest W. Seneka S. De Rademaeker M. et al.The reproductive outcome of female patients with myotonic dystrophy type 1 (DM1) undergoing PGD is not affected by the size of the expanded CTG repeat tract.J Assist Reprod Genet. 2010; 27: 327-333Crossref PubMed Scopus (11) Google Scholar]. Annelien Bredenoord, The Netherlands, addressed the issue of genetic risks in diseases caused by mutations in the mtDNA. Depending on the number of mutated mitochondria (degree of heteroplasmy), the recurrence risk to offspring can be unpredictable which has major ethical implications. Reproductive options for carriers of mtDNA mutations include prenatal diagnosis, PGD, or oocyte donation. Mitochondrial gene replacement may become available in the future [[41]Bredenoord A.L. Braude P. Ethics of mitochondrial gene replacement: from bench to bedside.BMJ. 2010; 341: c6021Crossref PubMed Scopus (10) Google Scholar]. Although generally morally acceptable, all these reproductive options for carriers of mtDNA mutations have limitations, mostly due to remaining uncertainties. Generally speaking, medical assisted reproduction is morally acceptable in mitochondrial disease as long as the child has a reasonable chance of an acceptable quality of life and efforts are made to reduce the risks as much as reasonably possible [[42]Bredenoord A.L. Dondorp W.J. Pennings G. De Die-Smulders C.E.M. Smeets H.J. De Wert G. Preimplantation genetic diagnosis for mitochondrial DNA disorders. Ethical guidance for clinical practice.Eur J Hum Genet. 2009; 17: 1550-1559Crossref PubMed Scopus (30) Google Scholar]. Sabine Rudnik-Schöneborn and Carina Awater, Germany, introduced the study design in Germany where a pro- and retrospective assessment of pregnancy and delivery in patients with various hereditary NMDs has been conducted since the early 1990s. It requires active participation of patients and has been successfully applied to many different conditions. Meanwhile the study group includes 180 patients of five major disease categories (myotonic dystrophy, muscular dystrophy, CMT disease, SMA, congenital myopathies) and 12 patients of other diagnoses. There was consensus among the workshop participants that those patients who contemplate a pregnancy within the study period should be prospectively followed within and after pregnancy by regular clinical examination, but this has not yet been realised due to limited resources. Fiona Norwood gave a brief outline on the forthcoming national pregnancy database in the UK, aimed at collecting data from pregnant women with muscle disease ± myasthenia gravis. This project is in the early stages of development but has secured some grant funding and ethical approval is in progress. Anne Kjersti Daltveit, Norway, reported on the the Medical birth registry of Norway (MBRN) which was established in 1967 in the wake of the thalidomide catastrophe. The specific objective was to detect, as soon as possible, increased rates of birth defects, and in general, to establish a basis for epidemiological research of perinatal health problems (http://www.fhi.no/eway/default.aspx?pid=238&trg=MainArea_5811&MainArea_5811=5895:0:15,3320:1:0:0:::0:0). It had recorded 2.7 million births after 12 weeks gestation up to 2010. Main maternal health problems, such as a pre-existing NMD, can be extracted from a general code and have to be further evaluated in the medical files. Another related study is the Norwegian mother and child cohort study (MoBa) where 100.000 pregnancies were documented by 2008 (http://www.niehs.nih.gov/research/atniehs/labs/epi/studies/moba/index.cfm). The study is based on questionnaires to the mother and father, with biological specimens being collected from mother, father and child. The main purpose of the study is to find causes of serious diseases in mothers and children. Many important epidemiological studies around pregnancy, delivery and the perinatal period have been published out of these registers, also in the field of NMD. Hanns Lochmüller gave a brief overview of the main TREAT-NMD activities, e.g. registry of outco