Marfan s Disease in Pregnancy A Review Of Five Recent Cases and a Consideration of Guidelines. Dr Len Kliman.
Antoine Bernard-Jean Marfan (1858-1942). Son of a provincial medical practitioner who discouraged his son from entering medicine. Entered the medical school in Toulouse after his father acquiesced. Internship in Paris after completing his military service. Developed an interest in paediatrics and was the first professor of infantile hygiene at the University of Paris. Co-author of Treatise of Children s Diseases. In 1896 presented the case of Gabrielle P at a meeting in Paris-Gabrielle had disproportionately long limbs and spider-like fingers and toes. Marfan called the condition dolicostenomely. A detailed review of the case suggests Gabrielle had congenital contractural arachnodactyly and not Marfan,s disease (Hecht and Beals 1972). The phenotype was expanded with time to include the cardiac and ocular lens anomalies. The term Marfan s Syndrome was first used by Henricus Weve in 1931.
The Genetics of MFS. The incidence of MFS is reported to be 1 in 3000 to 5000 individuals. MFS is a multisystem disease with a wide range of clinical severity. It is an autosomal dominant condition. MFS is due to a mutation in the FBN1 gene-first mutation reported in 1991 and since then over 1000 different mutations have been reported. This is inherited in 70 percent of individuals but in 30 percent of cases MFS results from a de novo mutation. In about 10 percent of patients with a typical MFS phenotype the mutation is not in the FBN1 gene, some of these patients have no identifiable gene mutation, some have a mutation in a gene encoding for TGF-B. Some of the patients with a proven FBN1 mutation have mild variants of MFS. FBN1 is a large gene (65 exons) located on chromosome 15. The protein that it codes for FBN1 protein is altered by the presence of mutations which results in abnormal protein folding by altering the bonding between cysteine residues within the microfibril. The FBN1 protein is an important and essential component of elastic and non-elastic connective tissue.
Pathophysiology of MFS. As previously discussed abnormal folding of FBN1 protein plays a part in the pathophysiology of MFS. However experiments by Dietz et al have shown the pathogenesis of especially the cardiac, pulmonary, lens and skeletal anomalies is due to abnormal levels of activation of TGF-B. TGF-B is a potent stimulator of inflammation, fibrosis and activator of certain matrix proteinases. Excess TGF-B activation in tissues is associated with failure of lung septation, myxomatous mitral valves and aortic root dilatation in mice given mutations in the FBN1 gene. Therefore the phenotypic features of MFS are due to structural microfibril/matrix abnormalities and dysregulation of matrix homeostasis mediated by excess TGF-B. Are particular genotypes associated with more severe phenotypic anomalies-mutations in central exons and exon skipping tends to be associated with more severe disease.
The Diagnosis of MFS. The cardinal features of MFS are aortic root dilatation and ocular lens dislocation. However numerous minor clinical features can be associated with MFS. Strict criteria for the diagnosis of MFS-the Ghent criteria were first proposed in1996 and revised in 2010. The Ghent criteria place the greatest weight on: - aortic root dilatation. - ectopia lentis. - presence of a mutation in the FBN1 gene. The criteria also includes numerous other systemic features which form part of the scoring system including- Dural ectasia, scoliosis or kyphosis of the spine,mitral valve prolapse, facial features and other skeletal anomalies. Mutations in the FBN1 gene have been found to be present in 95 percent of individuals meeting the Ghent criteria.
Thumb Sign of MFS.
Wrist sign of MFS.
Ectopia Lentis.
Typical Phenotype of MFS.
MFS and Pregnancy. Pregnancy poses special risks to patients with MFS primarily due to the risk of maternal death as a result of aortic dissection. The exact risk of dissection is still debatable but on the basis of a meta-analysis of the 3 prospective studies on the changes in the ascending aorta in pregnancy the risks are thought to be: -1 percent if the aortic diameter is < 4cm. -!0 percent if the aorta is > 4cm. (especially if >4.5cm ). The risk of aortic dissection occurs especially in: - the third trimester (50%). - in the first 6 weeks postpartum (33%). The increased risk of aortic dissection in pregnancy is presumed to be due to the hypervolemic and hyperdynamic circulation as well as the proven hormonally mediated changes in the aortic wall integrity with alterations in mucopoylsaccharides and elastin fibres. Aortic root dilatation in pregnancy may result in worsening aortic regurgitation.
Pregnancy and Aortic Growth. 80% of patients with MFS have some cardiovascular involvement. Three prospective studies looking at aortic growth in pregnancy in patients with MFS. In 145 pregnancies in 78 non-operated women with MFS there were no type A dissections. In 29 pregnancies in women with aortic root diameters of > 44mm there were 4 major cardiovascular complications; one type B dissection,2 carotid artery dissections and 1 patient with worsening aortic regurgitation. Growth of the aortic root occurs as a normal phenomenon in healthy women in pregnancy and persists till 6 weeks postpartum. Donnelly et al showed the aortic root growth rate is greater in patients with MFS compared to controls. However the risk of aortic dissection in patients with an ARD of 45mm or less is low-less than one percent. Women with a history of a previous aortic dissection are thought to be high risk but unable to quantify the risk.
Pregnancy and Aortic Growth. Pregnancy has been shown to have a deleterious effect on long-term aortic growth in women with MFS compared to women with MFS who have never conceived. On average over 20 years there is a 7mm versus 3mm increase in ARD which can be significant-especially in patients with an ARD of over 40mm. Women with MFS who have been pregnant are more likely to need an aortic repair in later life, and the repair is more likely to be needed at a younger age. Donnelly et al J Am Coll Card. 2102. Meijboom et al Am J Cardiol.2005. Rossiter et al Am J Obstet Gynecol. 2005.
Obstetric Complications with MFS. 142 pregnancies in 63 women. 28 miscarriages-20% rate. Premature delivery 15%-mainly due to PROM or cervical incompetence.(8%). Perinatal Mortality of 7.1%. (1%). 40% of all pregnancies had a maternal or fetal complication. An increased risk of postpartum haemorrhage and uterine inversion has also been reported. Meijboom LJ et al Int. J Cardiol.2006.
Management Principles. Pre-pregnancy Counselling: -genetic testing-pgd-3 months to develop test. -CVS/amniocentesis. -even with genetic testing discuss variable phenotype. -no accurate way of predicting the severity of the phenotype by the mutation found. -fetal echocardiography. Baseline assessment of the degree of cardiovascular involvement especially the severity of ARD-all patients with MFS should have a baseline TTE prior to conceiving. ARD > 45mm aortic repair prior to conceiving.
Management Principles. Monitor ARD in pregnancy. -ARD < 40mm TTE in each trimester. -ARD > 40mm TTE every 4-8 weeks (ECS.) -ARD > 40mm TTE every 2-4 weeks (ACC.) MRI best modality especially if entire aorta to be visualized. Beta-blockers have been shown to slow aortic growth-labetalol or metoprolol. Losartin an angiotensin receptor antagonist is an inhibitor of TGF-beta receptors and has been shown to reduce cardiovascular complications in MFS. But contraindicated in pregnancy.
Management of Labour. Especially if ARD > 40mm deliver in centre where cardiovascular surgery is available. Elective Caesarean section if: -ARD >40mm. -history of previous aortic dissection. -expanding ARD in the pregnancy. In labour: -avoid hypertension, keep systolic< 130mm. -adequate analgesia-epidural-90% of MFS patients have lumbosacral dural ectasia. Anaesthetic consult and MRI assessment. Increased risk of dural puncture and inadequate anaesthesia.
Dural Ectasia.
Management of Labour. Shorten second stage. Antibiotic prophylaxis only if: -previous endocarditis. -mechanical valve. Pregnancy related cardiovascular changes don t resolve for 6 months postpartum. -continue beta-blockers. -continue ARD measurements.
Five Recent Patients with MFS. Patients delivered within 18 months. All primigravid. All under the care of a Cardiologist and all seen by a Geneticist. All shown to have a mutation in the FBN-1 gene. 4/5 had a family history and one presumed to have a de novo mutation. All chose to have IVF with PGD. All 5 had phenotypic features of MFS including pectus carinatum, increased arm span to height ratio, facial features and ectopia lentis. All met Ghent criteria for MFS diagnosis.
Five Recent Patients with MFS. 3 patients with a previous aortic root repair and one of these with an aortic valve replacement and pacemaker for CHB. One patient presented at 8 weeks gestation with an ARD of 47mmgiven 10% risk of aortic dissection. TOP and pregnant 6 months later. No PROM, cervical incompetence or PNM. One with significant PE. All on beta-blockers and all had TTE in each trimester with no change noted in ARD.
Five Recent Patients with MFS. 4/5 had an elective Caesarean section: -2 patient preference. -1 due to PE. -1 recent aortic root repair. All patients remained on beta blockers postpartum and continued cardiac follow-up.
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