Neonatal Lupus

Research Registry for Neonatal Lupus

Neonatal Lupus (Text of article appearing in Systemic Lupus Erythematosus in Clinical Practice 2000;3:1-3, Published by The Lupus Foundation of America, Inc.)

Jill P. Buyon, M.D.

The problem: antibodies against self

Antibodies are a critical part of the body's defense against infection by foreign invaders such as bacteria and viruses. During pregnancy, antibodies in the mother's circulation are transported across the placenta into the bloodstream of the developing fetus.  The movement of these maternal antibodies begins at about 12-14 weeks of pregnancy.  This transport process is essential because the fetus is unable to make antibodies on its own. Thus, it is completely dependent on maternal antibodies to fight infection.

Unfortunately, the placenta cannot distinguish between antibodies that are helpful to the fetus and those that are not.  In women with autoimmune diseases, such as systemic lupus erythematosus (SLE) and Sjogren's Syndrome (SS), abnormal antibodies directed against "self" molecules also can cross the placenta from the mother and enter the fetal circulation. Known as autoantibodies, these are the hallmark of an autoimmune disease.

Autoantibodies are directed against many self-proteins. Specific autoantibodies may be particularly dangerous to the growing fetus and newborn child. For unknown reasons, in neonatal lupus the attack is targeted to heart tissue, skin, liver and blood elements.

Listening to the heartbeat
The most serious of these problems is permanent congenital heart block (also called third degree heart block) which may be life-threatening. In heart block, the normal electrical signal that stimulates the heartbeat is damaged by the maternal autoantibodies (or other as-yet-unidentified associated factors). The result is an abnormally slow heartbeat.  This is most often detected between 20 and 30 weeks of fetal development, with the 23rd-24th week being the most vulnerable.  This slow fetal heart rate can be identified by routine examination using a Doppler fetal heart rate monitor, obstetrical sonogram, or special fetal echocardiogram.

In almost all cases the heart block occurs as an isolated problem, i.e., there are no structural deformities of the heart.  Curiously, the presence of these autoantibodies is not associated with heart problems in the mother, but only in her child.

Skin rash
In contrast to the heart, which becomes damaged during pregnancy, the skin rash is generally observed only after birth, most commonly in the first to second month of life. It is important to note that the skin rash can be triggered by sun exposure. The rash often appears around the eyes, face, and scalp. It is generally very red and can have a circular appearance.

The child also should be checked for liver abnormalities and low blood counts (low white blood cells and platelets), although these are extremely rare problems.  Like the rash, these abnormalities are not permanent. Most affected children have either heart block or skin rashes, but some do have both. And, while early studies suggested that girls might be more often affected by the rash, recent large studies show that both sexes are equally susceptible to both rashes and congenital heart block.

Neonatal lupus': a confusing term
The name given to these fetal and neonatal illnesses is neonatal lupus. The term is extremely misleading.  The name originated because the skin rash resembled the cutaneous lesions seen in adults with SLE.

Several decades ago, in the earliest reports on congenital heart block, it was noted that many mothers had SLE. However, we now know that many of the mothers who have affected children are themselves totally asymptomatic and only have the anti-Ro and/or anti-La antibodies in their blood. Just because a mother has anti-Ro or La antibodies and a child with neonatal lupus does not mean she has SLE or SS.

Moreover, the child with heart block and/or skin rash does not have SLE but rather a distinct disease acquired from the passage of maternal autoantibodies.  Therefore, the name "neonatal lupus" is not very accurate. Neonatal lupus is not a true systemic disease (i.e., a disease involving multiple organ systems over time).

Anti-SSA/Ro and anti-SSB/La antibodies
The harmful antibodies identified thus far by numerous investigators are directed against normal cellular components called Ro, or Sjogren's syndrome A (SSA), and La, or Sjogren's syndrome B (SSB). The Ro and La proteins are thought to exist together in a single particle which is present in all cells. Therefore, it is difficult to explain why fetal organs other than the heart, skin, liver, and blood elements are not damaged.

Ro is composed of two separate proteins of different size–they are referred to by their molecular weights: 52 kD (the abbreviation for kilodaltons) and 60 kD. La, a third protein, is 48kD.

Antibodies to Ro and La occur with high frequency in individuals with SS: approximately 60-100 percent. They are less common in SLE: anti-Ro, about 40 percent and anti-La, about 15 percent.  Antibodies to the 52Ro protein are more common in SS than SLE.  With regard to neonatal lupus, it is not certain which exact antibody – anti-52Ro, anti-60Ro or anti-48La – is the most important, but anti-52Ro has received considerable attention.

Testing for antibodies
Every woman with SLE and/or SS should be tested for all of these antibodies as part of pre-pregnancy counseling.  If the antibodies are identified, special fetal cardiac monitoring can be done during pregnancy.

Some tests are able to detect very small amounts of these antibodies.  This is important, because at the present time it is not certain whether it is the quantity of antibody or an as-yet-unknown quality of the antibody that is critical in causing fetal heart damage and skin rashes. 

The patient's serum is used for all testing. (Serum is the clear liquid part of the blood that is present after the blood clots, and does not contain cells.)  The lest sensitive test, call immunodifffusion, may not detect very low levels of antibodies. The most widely used test today, the enzyme-linked immunosorbent assay (ELISA), is more sensitive than the immunodiffusion. In this test, a patient's serum is analyzed for antibodies against highly purified forms of Ro and La.  However, many commercial ELISAs do not distinguish between the 52 and 60 forms of Ro.

A third test is called the immunoblot or Western blot. This test can distinguish antibodies to the two different components of Ro, although it detects the 52Ro better than the 60Ro.

More about ELISA and immunoblot
The ELISA is available in commonly used commercial laboratories and most university medical centers. The immunoblot test is less readily available. If required, serum can be safely sent by normal mail delivery to specialized centers. In the author's experience, immunoblot may be helpful in addition to ELISA, for the following reasons.

Women whose serum contains anti-Ro antibodies, but who have the three special characteristics listed below, may be a lower risk for having a child with heart block than other women with anti-Ro antibodies: 1) when their serum is tested by ELISA, they only have low levels of antibodies to Ro; 2) by ELISA or immunoblot, they have no associated anti-La antibodies; and 3) by immunoblot, they do have antibodies to the 52Ro.

While heart block has never been associated with any autoantibodies other than anti-Ro and anti-La, the skin rash has on rare occasion been associated with antibodies to another cellular protein, called RNP (ribonucleoprotein).

The risk of having an affected child
If a mother's serum is found to contain antibodies against Ro and La, what then is the risk of having a baby with cardiac (heart), cutaneous (skin), or hematologic (blood) symptoms of neonatal lupus?

There is some controversy regarding the exact percentages, but generally the chances for heart block are between 1 and 5 in 100 pregnancies if a mother has anti-Ro or La antibodies (perhaps lower if immunoblot is negative). It is very puzzling that many women with these same antibodies have totally healthy children. This is an area of continuing scientific investigation.  Although 1-5 percent appears to be a low risk, it is far higher than the reported incidence of heart block in the population at large, i.e., mothers without antibodies.

The clinical approach to an at-risk mother
Once the mother's risk is identified, what should be done to prevent damage to the fetus? Part of the answer depends on whether it is a first pregnancy or whether heart block or any other sign of neonatal lupus has happened before in one of her children. If it is a first pregnancy a conservative approach is warranted, specifically use of an echocardiogram. This specialized sonogram of the heart gives a far better picture than routine obstetrical ultrasound. The echocardiogram should be performed first between the 16th and 18th week of pregnancy, then repeated every week, if possible, until at (or about) the 26th week. From this point on, routine obstetrical care, such as listening to the baby's heart rate, may be sufficient.

Heart block and the fetus
Should a problem be detected in the fetal heart, therapies may be necessary to try to lower antibody levels or simply to treat the heart condition.  However, the situation is a bit of a "Catach-22" –once established, complete heart block is not likely to be reversed.  (Sometimes the block is not complete, which is better). The outcome for the fetus at this point ranges from death in utero (information from several studies suggests this occurs in approximately 15 percent of cases) to a normal life without even a pacemaker. Thus, managing a first pregnancy is difficult, given the varying outcomes and the rarity of the disease.

For a mother with known antibodies who already has had a child with heart block, the risk of having a second affected child may be as high as one in six. Information from the national Research Registry for Neonatal Lupus shows there have been only 10 cases of heart block out of 70 pregnancies that followed the birth of a child with heart block.

It is possible to have one child with heart block and a second child with a rash, and vice versa. Do the odds justify aggressive management in the early weeks of pregnancy? This is a very unsettled issue. Still, the fact remains that the majority of fetuses will not develop heart block. Therefore, the use of procedures such as plasmapheresis and/or medications such as steroids prior to detection of a problem is not justified at this time. Future studies will address whether there may be a way that echocardiograms can identify which fetus might develop heart block.

Therapies for fetal heart block
If the fetus is found to have third degree (complete) heart block without any signs of heart failure—from the heart not pumping enough blood—our policy usually is just to watch and perform weekly echocardiograms.

If the fetus is in second degree block (incomplete), it may be of benefit to treat the mother with a steroid such as dexamethasone. Because this drug can cross the placenta and do into the fetal circulation, it potentially could reverse second degree block before it becomes third degree.  The rationale is to decrease cardiac inflammation before permanent scarring occurs.  This excellent outcome has been demonstrated in only a few cases; unfortunately, in almost all situations the block is already complete at the time it is first identified.

If the fetus shows additional signs of inflammation, such as fluid around the heart, lungs or abdomen, this is more serious and the fetus may need treatment with dexamethasone. However, more research is needed before definite recommendations can be made.

Long-term outlook
The prognosis for the child with heart block is generally good. Still, the heart block is permanent, and in some cases the condition is fatal. In the author's experience with 113 such children, 22 (19 percent) died.  The majority of the deaths were very early in life when the infants were less than 3 months old. Most children require pacemakers, which probably are needed for life.  Again, in the author's experience to date of 107 live-born children with complete heart block, 67 (63 percent) required pacemakers. In another study from Canada, 38 (57 percent) of 67 children have required pacemakers. Pacemakers often are implanted in the first three months of the baby's life.

For the child with only skin manifestations of neonatal lupus, the prognosis is excellent.  The rash generally disappears by about eight months. In most cases no medications are needed and no scars or marks are left. Happily, there is no evidence to suggest that children with neonatal lupus will develop SLE later in life.  Nevertheless, any child born to a mother with SLE does have a higher risk of developing lupus, especially if the child is a girl, although the chances are probably not more than one in 10.

Research Registry for Neonatal Lupus
In September 1994, the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) established a national Research Registry for Neonatal Lupus, in conjunction with the Hospital for Joint Diseases in New York. The purpose of the Registry is to gather information on a large number of affected children and their mothers. These data will: 1) provide answers to many clinical questions; 2) be used to plan clinical studies to establish optimal treatment; and 3) provide material for basic research to identify the exact cause of the heart and skin injury.

So far, 237 mothers and their 272 affected children have enrolled.  Permission is sought from each mother to obtain all pertinent medical records and, in some cases, serum for antibody testing and DNA for genetic analysis.  The Registry has been a successful effort, and is the only mechanism by which rare diseases can be properly studied.

Conclusions
In summary, the presence of antibodies to Ro and La poses a risk, albeit small, to the developing fetus.  The Research Registry for Neonatal Lupus is supported by a contract from NIAMS. Anyone interested in enrollment or with questions relating to neonatal lupus is welcome to contact: zoey.smith@nyumc.org.

Dr. Jill P. Buyon is Vice Chair of the Department of Rheumatology at the Hospital for Joint Diseases (HJD) Orthopaedic Institute in New York, NY, and Director of the HJD's Lupus Clinic and Research Registry for Neonatal Lupus.  She is a professor of Medicine at the NYU School of Medicine. Dr. Buyon recently accepted a three-year position on the Lupus News Medical Advisory Board.