Developed by Judith Pratt Rossiter, MD, Director of the Perinatal Center, St. Joseph Medical Center, Towson, MD.
Content approved by the NMF Professional Advisory Board.


What is the Marfan syndrome and why is it important for obstetricians to be aware of it?

The Marfan syndrome is a potentially life-threatening genetic disorder that affects the body’s connective tissue which results in a wide range of clinical severity associated with the cardiovascular, ocular, musculoskeletal, pulmonary, skin and central nervous systems. More than 200,000 Americans have the Marfan syndrome or a related disorder. Women with the Marfan syndrome who have marked enlargement of the aorta may be at risk for aortic dissection and sudden death. In addition, women who have already had aortic surgery generally require highly specialized care and follow-up in tertiary care settings for discussion of pregnancy issues, issues surrounding anticoagulation, and management of pregnancy and delivery.

The life-threatening aspect of the Marfan syndrome is the risk of enlargement of the aorta, the large blood vessel that leads away from the heart. Without medications and, in some cases, surgery, the aorta can tear or rupture, which can be fatal.

It is important for obstetricians to be aware of the Marfan syndrome because of the risks that pregnancy can pose for a woman who has the disorder. The obstetrician, in conjunction with other specialists (including a cardiologist, orthopedist, clinical geneticist and genetic counselor), can identify potential risks to help a woman with the Marfan syndrome decide if pregnancy is appropriate and safe, and how best to manage their pregnancy.

In addition, because many people with the Marfan syndrome have not yet been diagnosed, obstetricians should be aware of the outward skeletal signs of the disorder and, if there is a suspicion of the Marfan syndrome, refer the woman for additional evaluation to determine if she has the condition.

What is the cause of the Marfan syndrome?

The Marfan syndrome results from a mutation in the fibrillin 1 (FBN1) gene on chromosome 15q-21.1. It is inherited in an autosomal dominant fashion. Patients with typical the Marfan phenotype harbor different mutations involving the FBN-1 gene. To date, no correlation between the specific type of FBN-1 mutation and clinical phenotype has been recognized.

How is the diagnosis of the Marfan syndrome made?

The diagnostic evaluation for the Marfan syndrome should be performed by physicians experienced with the condition. The diagnosis rests on several factors: a family history of the disorder, the presence of ocular abnormalities (especially lens subluxation), characteristic skeletal alterations (which includes tall stature as compared to the rest of the family, height-span and upper/lower segment disproportion, scoliosis and arachnodactyly), enlargement of the aortic root and ascending aorta, and other systemic alterations. It is possible to have some, but not all, of these characteristics and be diagnosed with the Marfan syndrome. As a result, diagnostic evaluation should include, at a minimum:

• Detailed medical and family history.
  
• Complete physical examination, including measurements of skeletal proportions.
  
• Eye examination by an ophthalmologist who uses a slit lamp to look for lens dislocation after fully dilating the pupil.
  
• Echocardiogram to evaluate the function of the heart valves and the size of the aortic root.

This series of steps is important, not only in determining the diagnosis, but also in detecting problems that require immediate attention or long-term management. The Marfan syndrome is often a progressive condition and the signs may be subtle at first. In selected circumstances, molecular testing can serve as a useful adjunct to a comprehensive clinical evaluation for the diagnosis.

Pre-Pregnancy

Issues Regarding the Mother

The parents need to consider the medical condition of the mother and the chance of having an affected child when making the decision to have a child. In almost all circumstances, it is inappropriate for the physician or health professional to unilaterally decide that affected women should not attempt pregnancy.

What kind of evaluations, by which healthcare professionals, should an affected woman have prior to becoming pregnant?

Women with the Marfan syndrome should undergo a thorough physical examination by their primary care provider (family practitioner or internist) to assess their general physical condition. In addition, an echocardiogram should be performed by a cardiologist who is capable of interpreting aortic root diameters, as the dilation of the aortic root is the single greatest predictor of pregnancy outcome. Ideally, consultation with a perinatologist should be arranged to discuss obstetric issues specific to the Marfan syndrome.

A clinical geneticist or genetic counselor should also be consulted if the potential mother or father is affected with the Marfan syndrome. The genetics professional can help the couple to understand the possible outcomes resulting from the inheritance pattern of the Marfan syndrome and take the time to explore in-depth the options available to them and the implications for their decisions.

What clinical findings in an affected woman significantly increase maternal risk during pregnancy? Are there situations where pregnancy is definitely discouraged?

All women with the Marfan syndrome are at increased risk for complications during pregnancy. Any woman with the Marfan syndrome who becomes pregnant should be cared for by an obstetrician with the experience and expertise needed to manage potentially life-threatening cardiovascular complications.

Current evidence suggests that women with a maximal aortic dimension less than 4.0 cm are at very low risk for a rapid change in aortic size or aortic tear during or immediately after pregnancy. Women with aortic dimensions above 4.0 cm are at greater risk, and this risk appears to increase proportionally to aortic size.

It is important to note that these conclusions are based upon relatively small studies and that each person with the Marfan syndrome has a unique set of circumstances that dictate their risk of complication during pregnancy. Few hard and fast rules apply. These include:

• A woman with the Marfan syndrome who will not tolerate any increase in risk for aortic tear or rupture should not become pregnant.
  
  
• Any woman with the Marfan syndrome who becomes pregnant should be followed closely by her obstetrician and cardiologist. There should be a maximal interval between echocardiograms of three months.
  
  
• The overall risk associated with aortic measurement of 4.5 cm is greater than the risk associated with a measurement of 4.0 cm. The specific risk to a given individual is difficult to quantify and is not adequately reflected by aortic size alone. In consideration of the health of the mother and fetus, the risk associated with an aortic measurement in excess of 5.0 cm is extreme, and pregnancy is difficult to justify.

Are women with Marfan syndrome more likely to miscarry a pregnancy?

The miscarriage rate in women with the Marfan syndrome is no different than that in the general population. There are no studies that have related aortic root diameter to spontaneous pregnancy loss.

Issues Regarding the Child

What are the chances that the baby will have the Marfan syndrome?

When one parent has the Marfan syndrome, each child born has a 50-50 chance of being affected by the disorder, regardless of the sex of the child or the affected parent.

If a newborn with an affected parent exhibits signs of the Marfan syndrome at birth – even if there are not enough characteristics of the disorder to confirm the diagnosis – it is essential that the parents continue to have the baby examined on a regular basis to watch for development of additional signs of the Marfan syndrome. Early diagnosis and treatment of the various characteristics of the disorder can enable an affected person to live a normal life span.

Infants born to an unaffected parent (mother or father) that show overt skeletal or cardiovascular manifestations of the Marfan syndrome (such as extremely long extremities and digits or severe mitral valve prolapse with regurgitation) should have a comprehensive evaluation and will require follow-up. It should be noted that, while the Marfan syndrome is inherited in three-quarters of cases, it occurs as a result of a spontaneous mutation in the egg or the sperm in approximately 25 percent of people with the disorder.


During Pregnancy

What special care is needed during the pregnancy?

An echocardiogram should be performed prior to pregnancy and should be repeated a minimum of three times during pregnancy -- once in each trimester -- and once during the two months following pregnancy. In women whose aortic root diameter prior to pregnancy is close to 4 cm, more frequent echocardiograms are recommended (approximately every 6-8 weeks) to identify any sudden increase in aortic size. Women who experience a significant increase in their aortic root diameter during the course of the pregnancy should also have more frequent echocardiograms.

What are the special considerations for anticoagulation during the pregnancy, birth and postpartum period?

Women with the Marfan syndrome who have had aortic surgery with aortic and/or mitral valve replacement prior to pregnancy or other indications for anticoagulant therapy require special consideration. In the United States, anticoagulation during pregnancy is usually accomplished with subcutaneous injections of heparin.-. Heparin is a large molecule, does not cross the placenta and has not been associated with birth defects.

Most people who are on chronic anticoagulation receive Coumadin, a small molecule that interferes with the action of Vitamin K in the liver and reduces the efficiency of action of several clotting factors. Coumadin is taken orally and provides effective anticoagulation. Because it is a small molecule, Coumadin crosses the placenta and has been associated with birth defects called the fetal warfarin syndrome. This syndrome includes abnormalities of the eyes, nose, limbs and central nervous system, as well as loss of hearing. For this reason, Coumadin is not used during pregnancy in this country.

In Europe, a different strategy is used based on the known window of exposure during which fetal warfarin syndrome results (between about 7 and 11 weeks of gestation). Therefore, Coumadin is commonly continued until six weeks of pregnancy and then is discontinued from 6 weeks until 12 weeks, during which time most organ systems of the developing embryo form. Coumadin is then restarted at 12 weeks and continued until 36 weeks, when it is again discontinued and heparin used until delivery.

Heparin is rapidly metabolized during pregnancy so that full anticoagulation often requires three injections.. Frequent blood tests are required to confirm that anticoagulation is adequate. A relatively newer form of heparin, low molecular weight heparin, has been effectively used during pregnancy for many indications. However, low molecular weight heparin is not considered appropriate for anticoagulation for people with a mechanical heart valve during pregnancy.

To summarize, in the United States, women with the Marfan syndrome who require anticoagulation during pregnancy are generally placed on unfractionated heparin with twice or three times daily dosing and frequent monitoring of the activated prothrombin time (PTT) to confirm adequate anticoagulation. This is continued throughout the entire pregnancy, stopping briefly for 24-48 hours surrounding the time of birth. Coumadin can be safely used while breast-feeding because the levels in breast milk are very low and do not induce anticoagulation in the infant. Therefore, after delivery, heparin should be restarted and Coumadin also started. The heparin can be discontinued once the Coumadin has reached therapeutic levels. Pregnancy and the postpartum period are times of markedly increased risk of clot formation and, therefore, women who require anticoagulation should be fully anticoagulated throughout this time.

Can beta-blockers continue to be used throughout the pregnancy?

Many women with the Marfan syndrome, especially those who have moderate or marked aortic dilatation for age, are treated with beta-blockers to attempt to lower the risk of aortic enlargement and dissection. Beta-blockers can be continued throughout the pregnancy, but there are some considerations. There have been no reported teratogenic effects of beta-blockers. For this reason, beta-blocker use need not be avoided in the first trimester.

However, several studies have demonstrated a lower birth weight in infants exposed to beta-blockers in utero. Of the many beta-blockers, this effect appears to be greatest with atenolol (Tenormin), a commonly used beta-blocker for people with the Marfan syndrome. In addition, both atenolol and propranolol have been associated with transient neonatal effects, such as bradycardia and hypotension, which resolve within two days of delivery. As a result, infants who have been exposed to beta-blockers in utero should be closely monitored in the newborn period. Usually, this monitoring can be accomplished in a traditional nursery setting and does not require Intensive Care Nursery observation for an otherwise healthy infant. There shouldn’t be any problems unless an increased dose was initiated just before the delivery or hypovolemia becomes an issue. It is always best to have a pediatrician nearby who is alerted to the situation.

Beta-blockers may delay the rate of aortic dilatation in some women and also lengthen the time before interventional surgery is warranted in people with the Marfan syndrome. While some risks of continuing beta-blockers throughout pregnancy exist, the potential benefits of these medications likely outweigh the risks. Therefore, beta-blockers can be continued in most patients.

Are there any special orthopaedic concerns during pregnancy for women with the Marfan syndrome?

Joint laxity tends to increase as a pregnancy progresses. As a result, many women with the Marfan syndrome who have joint problems prior to pregnancy experience a worsening of these symptoms during pregnancy. This increase in discomfort frequently includes pain in the lower back, pelvis and legs that is exacerbated with walking and improves when sitting or reclining. Occasionally, the pelvic pain persists despite sitting or joint discomfort becomes too great, thus requiring bed rest for varying portions of the pregnancy.

Labor and Delivery

Is a vaginal or cesarean birth safer for a woman with the Marfan syndrome?

The several large studies describing the outcomes of pregnancies for women with the Marfan syndrome suggest that for women with aortic diameters less than 4.0 cm at the time of delivery are similar for vaginal and cesarean section delivery.

Recommendations for management of labor include:

• Epidural analgesia for the labor and delivery process to maintain stable blood pressures and avoid large fluctuations in blood pressure.
  
• Avoidance of involuntary Valsalva. Once the cervix has completely dilated, uterine forceps are then used to bring the baby’s head through the pelvis into the vaginal opening. Women with the Marfan syndrome should not push after the cervix is fully dilated. For delivery, either forceps or a vacuum extractor can be used to faciliate delivery and minimize the opportunity for the mother to "bear down" or "push."

There remains controversy regarding the management of delivery in women with more significant aortic dilation. It may be most prudent to deliver those patients by cesarean section without labor using epidural anesthesia.

Is epidural anesthesia safe for a woman with the Marfan syndrome? Does the presence of dural ectasia alter the recommendation for the use of an epidural?

Epidural anesthesia is safe for the vast majority of women with the Marfan syndrome. However, it is not advised for women with moderately severe dural ectasia. Dural ectasia causes the dura to balloon out, leaving virtually no epidural space. The chances of a spinal fluid (CSF) leak would seem to be high.

Care of the Newborn

What is the role of the pediatrician at the birth of the child?

At birth, the pediatrician should conduct a basic evaluation, as would be done for any newborn. The only pressing issue is the presence of severe mitral regurgitation, the most common cause of significant problems in infants with the Marfan syndrome who have a new mutation.

For the child, early assessment of visual acuity is important to be sure the ocular function develops normally. Because lens dislocation may be present at birth or shortly thereafter, a dilated eye exam is recommended in the neonatal period. In general, comprehensive evaluation of the child by the pediatrician is important and should be done in conjunction with evaluation by a geneticist, cardiologist, ophthalmologist and other specialists, as needed.

Is it possible to screen embryos for the Marfan syndrome prior to implantation in an in vitro pregnancy?

Prenatal diagnosis of the Marfan syndrome is available if the specific FBN1 mutation is known or, in some families, if markers linked to the FBN1 gene are informative. For many families, prenatal diagnosis presents a set of difficult decisions and the use or pre-implantation diagnosis is more appealing. Several centers in the United States offer this process, which is known as preimplantation genetic diagnosis (PGD). Most of the centers are University Centers with in vitro fertilization (IVF) programs, embryo manipulation capabilities and molecular genetics support. In order to provide preimplantation diagnosis, the specific Marfan mutation in the affected parent must be known or the mutant FBN1 gene must be identifiable by a closely linked molecular marker that has been identified by prior family studies.

The PGD process begins with IVF, as would be used for infertility patients. This includes medications to increase the number of eggs that are ovulated in a single cycle. Once these eggs appear to be mature by ultrasound, they are retrieved using ultrasound guidance and a needle that is placed through the vagina and into the ovarian tissue. These eggs are then exposed to sperm, which are collected by the male partner. Either fertilization occurs spontaneously or a single sperm is directly injected into an egg through a process called intracytoplasmic sperm injection (ICSI). The fertilized eggs then begin to divide while in culture. When the embryo reaches the 6-8 cell stage (2-3 days after fertilization), 1 or 2 cells are removed from the embryo. These cells are then analyzed for the Marfan syndrome mutation or marker using molecular genetic technology. Embryos apparently lacking the Marfan gene are selected for implantation in the uterus.

IVF for the indication of infertility is covered by some insurance policies and not others. Some coverage is based on state and state-specific insurance legislation. Far less commonly is IVF covered for patients who do not have infertility, as is often the case in couples at risk for an infant with Marfan syndrome. The availability of any of this technology is region-specific, with availability in many large cities, and rare in less densely populated regions of the country.