Evaluation of fetuses in a study of intravenous immunoglobulin as preventive therapy for congenital heart block: Results of a multicenter, prospective, open-label clinical trial

Abstract

Objective: The recurrence rate of anti-SSA/Ro-associated congenital heart block (CHB) is 17%. Sustained reversal of third-degree block has never been achieved. Based on potential reduction of maternal autoantibody titers as well as fetal inflammatory responses, intravenous immunoglobulin (IVIG) was evaluated as preventive therapy for CHB.

Methods: A multicenter, prospective, open-label study based on Simon's 2-stage optimal design was initiated. Enrollment criteria included the presence of anti-SSA/Ro antibodies in the mother, birth of a previous child with CHB/neonatal lupus rash, current treatment with < or = 20 mg/day of prednisone, and <12 weeks pregnant. IVIG (400 mg/kg) was given every 3 weeks from week 12 to week 24 of gestation. The primary outcome was the development of second-degree or third-degree CHB.

Results: Twenty mothers completed the IVIG protocol before the predetermined stopping rule of 3 cases of advanced CHB in the study was reached. CHB was detected at 19, 20, and 25 weeks; none of the cases occurred following the finding of an abnormal PR interval on fetal Doppler monitoring. One of these mothers had 2 previous children with CHB. One child without CHB developed a transient rash consistent with neonatal lupus. Sixteen children had no manifestations of neonatal lupus at birth. No significant changes in maternal titers of antibody to SSA/Ro, SSB/La, or Ro 52 kd were detected over the course of therapy or at delivery. There were no safety issues.

Conclusion: This study establishes the safety of IVIG and the feasibility of recruiting pregnant women who have previously had a child with CHB. However, IVIG at low doses consistent with replacement does not prevent the recurrence of CHB or reduce maternal antibody titers.

Trial registration: ClinicalTrials.gov NCT00460928.

Figure 1. Mechanical Doppler PR interval for CHB and non-CHB pregnancies

The figure illustrates the mean and SD calculated for each gestational week. For the non-CHB group, values between 16 and 34 weeks are shown. For the CHB group, only values prior to CHB detection are shown. The dashed lines represent the Mean + 3SD and the Mean − 3SD values respectively. The PR intervals for the CHB fetuses are all within normal range (Mean+/− 3SD) and thus 1^st degree block did not precede advanced CHB.

Figure 2. Antibody titers and IgG levels during pregnancy

There were no significant decreases in the titers of anti-SSA/Ro-SSB/La, anti-Ro52 or IgG levels in the mothers that received IVIG. Two of the women with affected pregnancies received only 3 IVIG doses and the third mother with an affected pregnancy only 4 doses; results are shown separately.