Watch Fetus In Presence of Anti-Ro/La Antibodies

NEW YORK — Any pregnant woman who has anti-Ro/La antibodies should have weekly fetal echocardiograms beginning at 16 weeks' gestation to look for possible signs of congenital heart block, Dr. Jill P. Buyon said at a rheumatology meeting sponsored by New York University.

During pregnancy these autoantibodies, which are typically found in high titers in patients with systemic lupus erythematosus (SLE) and Sjögren's syndrome, but also in some asymptomatic individuals, begin to cross the placenta as early as 11 weeks.

The autoantibodies accumulate in the fetal circulation and are associated with the development of various manifestations of neonatal lupus, particularly prolongation of the mechanical PR interval and congenital atrioventricular block.

The importance of early detection of these autoantibodies in the fetus is underscored by the fact that once third-degree, or complete, heart block has developed, it is irreversible with current therapies, according to Dr. Buyon, professor of medicine, department of rheumatology, New York University, New York City.

Moreover, anti-Ro/La congenital heart block carries a 20% mortality, and at present the majority of children who survive need a pacemaker.

Intense research interest therefore is focused on identifying markers of early cardiac injury, at a point before fibrosis and scarring are permanent, and on the potential for therapeutic interventions to reverse early changes.

The use of cardiac monitoring to detect prolongations of the PR interval greater than 150 milliseconds was recently evaluated in the observational PR Interval and Dexamethasone Evaluation (PRIDE) study of pregnant women who were positive for anti-Ro and/or anti-La antibodies. The study also attempted to provide some data on outcomes following the administration of steroids.

Fetal echocardiography was performed weekly between weeks 16 and 26, and then biweekly between weeks 26 and 34, according to Dr. Buyon, one of the study investigators.

She and her colleagues were looking for prolongation of the PR interval, evidence of tricuspid regurgitation, and unexplained atrial echodensities.

Among the 88 patients who completed an evaluable course, there were three cases of third-degree heart block.

One of these patients had a normal PR interval, but some tricuspid regurgitation was noted at 17 weeks and atrial echodensity, at 22 weeks.

A week later the fetus was in third-degree heart block and, despite treatment with maternal dexamethasone, 4 mg/day, severe hydrops developed and the pregnancy was terminated.

The second fetus had a normal PR interval between weeks 16 and 18 along with mild tricuspid regurgitation at week 17. The mother missed an appointment and, by the next time she was seen, third-degree block had developed in the fetus. This persisted despite administration of dexamethasone, and the child continued to be followed after birth (Arthritis Rheum. 2006;54:S689).

The third fetus also had a normal PR interval at 18 weeks, but 10 days later the fetus was in third-degree block and hydropic. Treatment with dexamethasone was unsuccessful, and the pregnancy was terminated at 20.5 weeks.

First-degree block was detected in an additional three fetuses. In one, the PR was normal at weeks 16–18, was prolonged at week 19, and normalized within 7 days of dexamethasone treatment.

The second had a prolonged PR interval at week 22 that resolved within 3 days of dexamethasone treatment. These two patients both had normal electrocardiograms at birth.

The third fetus had normal PR intervals throughout gestation but an electrocardiogram at birth showed first-degree block that has persisted to age 3 years.

Dexamethasone was also used in nine cases of second-degree block. Of these, four fetuses progressed to third-degree block, four remained in second, and one was born in normal sinus rhythm. “This was a little disappointing,” Dr. Buyon said.

Of the 79 neonates for whom birth electrocardiograms were available, 78 were normal, and all 46 for whom 1-year follow-up electrocardiograms were available were normal, she said.

In conclusion, the study suggests the following, according to Dr. Buyon:

▸ First-degree block in utero is reversible with dexamethasone, but if present at birth, close observation by a cardiologist is needed because of the possibility of later progression.

▸ There has not been evidence of conduction abnormalities developing later in neonates whose electrocardiogram was normal at birth.

▸ Advanced cardiomyopathy can occur within 7 days of a normal PR interval, so even a weekly evaluation may not always be sufficient.

▸ Tricuspid regurgitation may be an important early marker of injury.

Dexamethasone treatment poses significant hazards to both mother and fetus, with maternal risks including diabetes and hypertension, and fetal risks including intrauterine growth retardation, adrenal suppression, and decreased brain growth. Moreover, as was seen in PRIDE, efficacy is hardly guaranteed.

Accordingly, other therapeutic approaches are currently being investigated, including inhibition of transforming growth factor-β to limit fibrosis and prophylaxis with intravenous immune globulin (see box).

Next: IVIG for Heart Block Prevention?

Intravenous immune globulin (IVIG) has a history of safely being used in pregnancy, primarily for autoimmune thrombocytopenia and immune deficiency syndromes. A few cases of successful use in congenital heart block have also been reported.

To determine if this prophylactic approach could reliably decrease the placental transport of anti-Ro/SSA and anti-La/SSB antibodies, the Preventive IVIG Therapy for Congenital Heart Block (PITCH) trial is now enrolling patients. Sponsored by New York University School of Medicine and the Alliance for Lupus Research, the trial aims to enroll 19 women who are antibody positive and have already had a child with congenital heart block or a rash that might have been neonatal lupus. Such mothers are at much higher risk of having another child with congenital heart block than are mothers positive for anti-Ro/La who have not already had an affected child.

Participants will be given 400 mg/kg of IVIG every 3 weeks for a total of five treatments between weeks 12 and 24 of pregnancy. If fewer than three fetuses develop second- or third-degree heart block, another 35 women will be enrolled.

“Then, if there are fewer than six cases of heart block out of 54, we will be on the way to having a prophylactic therapy,” said Dr. Buyon, who is principal investigator for the trial.

Additional information about the PITCH trial is available online at

http://clinicaltrials.gov/show/NCT00460928

NEW YORK — Any pregnant woman who has anti-Ro/La antibodies should have weekly fetal echocardiograms beginning at 16 weeks' gestation to look for possible signs of congenital heart block, Dr. Jill P. Buyon said at a rheumatology meeting sponsored by New York University.

During pregnancy these autoantibodies, which are typically found in high titers in patients with systemic lupus erythematosus (SLE) and Sjögren's syndrome, but also in some asymptomatic individuals, begin to cross the placenta as early as 11 weeks.

The autoantibodies accumulate in the fetal circulation and are associated with the development of various manifestations of neonatal lupus, particularly prolongation of the mechanical PR interval and congenital atrioventricular block.

The importance of early detection of these autoantibodies in the fetus is underscored by the fact that once third-degree, or complete, heart block has developed, it is irreversible with current therapies, according to Dr. Buyon, professor of medicine, department of rheumatology, New York University, New York City.

Moreover, anti-Ro/La congenital heart block carries a 20% mortality, and at present the majority of children who survive need a pacemaker.

Intense research interest therefore is focused on identifying markers of early cardiac injury, at a point before fibrosis and scarring are permanent, and on the potential for therapeutic interventions to reverse early changes.

The use of cardiac monitoring to detect prolongations of the PR interval greater than 150 milliseconds was recently evaluated in the observational PR Interval and Dexamethasone Evaluation (PRIDE) study of pregnant women who were positive for anti-Ro and/or anti-La antibodies. The study also attempted to provide some data on outcomes following the administration of steroids.

Fetal echocardiography was performed weekly between weeks 16 and 26, and then biweekly between weeks 26 and 34, according to Dr. Buyon, one of the study investigators.

She and her colleagues were looking for prolongation of the PR interval, evidence of tricuspid regurgitation, and unexplained atrial echodensities.

Among the 88 patients who completed an evaluable course, there were three cases of third-degree heart block.

One of these patients had a normal PR interval, but some tricuspid regurgitation was noted at 17 weeks and atrial echodensity, at 22 weeks.

A week later the fetus was in third-degree heart block and, despite treatment with maternal dexamethasone, 4 mg/day, severe hydrops developed and the pregnancy was terminated.

The second fetus had a normal PR interval between weeks 16 and 18 along with mild tricuspid regurgitation at week 17. The mother missed an appointment and, by the next time she was seen, third-degree block had developed in the fetus. This persisted despite administration of dexamethasone, and the child continued to be followed after birth (Arthritis Rheum. 2006;54:S689).

The third fetus also had a normal PR interval at 18 weeks, but 10 days later the fetus was in third-degree block and hydropic. Treatment with dexamethasone was unsuccessful, and the pregnancy was terminated at 20.5 weeks.

First-degree block was detected in an additional three fetuses. In one, the PR was normal at weeks 16–18, was prolonged at week 19, and normalized within 7 days of dexamethasone treatment.

The second had a prolonged PR interval at week 22 that resolved within 3 days of dexamethasone treatment. These two patients both had normal electrocardiograms at birth.

The third fetus had normal PR intervals throughout gestation but an electrocardiogram at birth showed first-degree block that has persisted to age 3 years.

Dexamethasone was also used in nine cases of second-degree block. Of these, four fetuses progressed to third-degree block, four remained in second, and one was born in normal sinus rhythm. “This was a little disappointing,” Dr. Buyon said.

Of the 79 neonates for whom birth electrocardiograms were available, 78 were normal, and all 46 for whom 1-year follow-up electrocardiograms were available were normal, she said.

In conclusion, the study suggests the following, according to Dr. Buyon:

▸ First-degree block in utero is reversible with dexamethasone, but if present at birth, close observation by a cardiologist is needed because of the possibility of later progression.

▸ There has not been evidence of conduction abnormalities developing later in neonates whose electrocardiogram was normal at birth.

▸ Advanced cardiomyopathy can occur within 7 days of a normal PR interval, so even a weekly evaluation may not always be sufficient.

▸ Tricuspid regurgitation may be an important early marker of injury.

Dexamethasone treatment poses significant hazards to both mother and fetus, with maternal risks including diabetes and hypertension, and fetal risks including intrauterine growth retardation, adrenal suppression, and decreased brain growth. Moreover, as was seen in PRIDE, efficacy is hardly guaranteed.

Accordingly, other therapeutic approaches are currently being investigated, including inhibition of transforming growth factor-β to limit fibrosis and prophylaxis with intravenous immune globulin (see box).

Next: IVIG for Heart Block Prevention?

Intravenous immune globulin (IVIG) has a history of safely being used in pregnancy, primarily for autoimmune thrombocytopenia and immune deficiency syndromes. A few cases of successful use in congenital heart block have also been reported.

To determine if this prophylactic approach could reliably decrease the placental transport of anti-Ro/SSA and anti-La/SSB antibodies, the Preventive IVIG Therapy for Congenital Heart Block (PITCH) trial is now enrolling patients. Sponsored by New York University School of Medicine and the Alliance for Lupus Research, the trial aims to enroll 19 women who are antibody positive and have already had a child with congenital heart block or a rash that might have been neonatal lupus. Such mothers are at much higher risk of having another child with congenital heart block than are mothers positive for anti-Ro/La who have not already had an affected child.

Participants will be given 400 mg/kg of IVIG every 3 weeks for a total of five treatments between weeks 12 and 24 of pregnancy. If fewer than three fetuses develop second- or third-degree heart block, another 35 women will be enrolled.

“Then, if there are fewer than six cases of heart block out of 54, we will be on the way to having a prophylactic therapy,” said Dr. Buyon, who is principal investigator for the trial.

Additional information about the PITCH trial is available online at

http://clinicaltrials.gov/show/NCT00460928

NEW YORK — Any pregnant woman who has anti-Ro/La antibodies should have weekly fetal echocardiograms beginning at 16 weeks' gestation to look for possible signs of congenital heart block, Dr. Jill P. Buyon said at a rheumatology meeting sponsored by New York University.

During pregnancy these autoantibodies, which are typically found in high titers in patients with systemic lupus erythematosus (SLE) and Sjögren's syndrome, but also in some asymptomatic individuals, begin to cross the placenta as early as 11 weeks.

The autoantibodies accumulate in the fetal circulation and are associated with the development of various manifestations of neonatal lupus, particularly prolongation of the mechanical PR interval and congenital atrioventricular block.

The importance of early detection of these autoantibodies in the fetus is underscored by the fact that once third-degree, or complete, heart block has developed, it is irreversible with current therapies, according to Dr. Buyon, professor of medicine, department of rheumatology, New York University, New York City.

Moreover, anti-Ro/La congenital heart block carries a 20% mortality, and at present the majority of children who survive need a pacemaker.

Intense research interest therefore is focused on identifying markers of early cardiac injury, at a point before fibrosis and scarring are permanent, and on the potential for therapeutic interventions to reverse early changes.

The use of cardiac monitoring to detect prolongations of the PR interval greater than 150 milliseconds was recently evaluated in the observational PR Interval and Dexamethasone Evaluation (PRIDE) study of pregnant women who were positive for anti-Ro and/or anti-La antibodies. The study also attempted to provide some data on outcomes following the administration of steroids.

Fetal echocardiography was performed weekly between weeks 16 and 26, and then biweekly between weeks 26 and 34, according to Dr. Buyon, one of the study investigators.

She and her colleagues were looking for prolongation of the PR interval, evidence of tricuspid regurgitation, and unexplained atrial echodensities.

Among the 88 patients who completed an evaluable course, there were three cases of third-degree heart block.

One of these patients had a normal PR interval, but some tricuspid regurgitation was noted at 17 weeks and atrial echodensity, at 22 weeks.

A week later the fetus was in third-degree heart block and, despite treatment with maternal dexamethasone, 4 mg/day, severe hydrops developed and the pregnancy was terminated.

The second fetus had a normal PR interval between weeks 16 and 18 along with mild tricuspid regurgitation at week 17. The mother missed an appointment and, by the next time she was seen, third-degree block had developed in the fetus. This persisted despite administration of dexamethasone, and the child continued to be followed after birth (Arthritis Rheum. 2006;54:S689).

The third fetus also had a normal PR interval at 18 weeks, but 10 days later the fetus was in third-degree block and hydropic. Treatment with dexamethasone was unsuccessful, and the pregnancy was terminated at 20.5 weeks.

First-degree block was detected in an additional three fetuses. In one, the PR was normal at weeks 16–18, was prolonged at week 19, and normalized within 7 days of dexamethasone treatment.

The second had a prolonged PR interval at week 22 that resolved within 3 days of dexamethasone treatment. These two patients both had normal electrocardiograms at birth.

The third fetus had normal PR intervals throughout gestation but an electrocardiogram at birth showed first-degree block that has persisted to age 3 years.

Dexamethasone was also used in nine cases of second-degree block. Of these, four fetuses progressed to third-degree block, four remained in second, and one was born in normal sinus rhythm. “This was a little disappointing,” Dr. Buyon said.

Of the 79 neonates for whom birth electrocardiograms were available, 78 were normal, and all 46 for whom 1-year follow-up electrocardiograms were available were normal, she said.

In conclusion, the study suggests the following, according to Dr. Buyon:

▸ First-degree block in utero is reversible with dexamethasone, but if present at birth, close observation by a cardiologist is needed because of the possibility of later progression.

▸ There has not been evidence of conduction abnormalities developing later in neonates whose electrocardiogram was normal at birth.

▸ Advanced cardiomyopathy can occur within 7 days of a normal PR interval, so even a weekly evaluation may not always be sufficient.

▸ Tricuspid regurgitation may be an important early marker of injury.

Dexamethasone treatment poses significant hazards to both mother and fetus, with maternal risks including diabetes and hypertension, and fetal risks including intrauterine growth retardation, adrenal suppression, and decreased brain growth. Moreover, as was seen in PRIDE, efficacy is hardly guaranteed.

Accordingly, other therapeutic approaches are currently being investigated, including inhibition of transforming growth factor-β to limit fibrosis and prophylaxis with intravenous immune globulin (see box).

Next: IVIG for Heart Block Prevention?

Intravenous immune globulin (IVIG) has a history of safely being used in pregnancy, primarily for autoimmune thrombocytopenia and immune deficiency syndromes. A few cases of successful use in congenital heart block have also been reported.

To determine if this prophylactic approach could reliably decrease the placental transport of anti-Ro/SSA and anti-La/SSB antibodies, the Preventive IVIG Therapy for Congenital Heart Block (PITCH) trial is now enrolling patients. Sponsored by New York University School of Medicine and the Alliance for Lupus Research, the trial aims to enroll 19 women who are antibody positive and have already had a child with congenital heart block or a rash that might have been neonatal lupus. Such mothers are at much higher risk of having another child with congenital heart block than are mothers positive for anti-Ro/La who have not already had an affected child.

Participants will be given 400 mg/kg of IVIG every 3 weeks for a total of five treatments between weeks 12 and 24 of pregnancy. If fewer than three fetuses develop second- or third-degree heart block, another 35 women will be enrolled.

“Then, if there are fewer than six cases of heart block out of 54, we will be on the way to having a prophylactic therapy,” said Dr. Buyon, who is principal investigator for the trial.

Additional information about the PITCH trial is available online at

http://clinicaltrials.gov/show/NCT00460928