High Dose Immunoglobulin During Pregnancy For Recurrent Neonatal
Hemochromatosis
Peter F.
Whitington, MD
Department of
Pediatrics
The Feinberg
School of Medicine of Northwestern University
Children's
Memorial Hospital
Chicago, IL
Judith U.
Hibbard, MD
Department of
Obstetrics and Gynecology
The Pritzker
School of Medicine
The University
of Chicago
Chicago, IL
Abstract
Background:
Neonatal hemochromatosis (NH) is a rare disease of gestation
that results in severe fetal liver injury. We hypothesized an
alloimmune etiology for NH based on its high recurrence rate in
sibships. In this study, we assessed the effectiveness of
administering high-dose intravenous immunoglobulin derived from
pooled serum of multiple donors (IV-Ig) during pregnancy to
prevent or alter the severity of recurrent NH.
Study design:
Women whose most recent pregnancy ended in documented NH were
treated with IV-Ig, 1 g/kg body weight weekly from the 18th
week until the end of gestation. The outcomes of treated
pregnancies were compared to the outcomes of randomly selected
previous affected pregnancies for each woman, which were used as
historical controls.
Results:
Fifteen women were treated through 16 pregnancies. All
pregnancies progressed uneventfully and resulted in live babies
with normal physical examinations and birth weights that were
appropriate for gestational age. Twelve babies had evidence of
liver involvement with NH: eleven had elevated serum
a-fetoprotein
and ferritin levels or elevated serum
a-fetoprotein,
including 4 with coagulopathy (INR > 1.5), and one had
coagulopathy alone. All babies survived with medical or no
treatment and are currently healthy. When analyzed on a
per-mother basis comparing outcomes of treated gestations to
randomly selected previous affected gestations, gestational IV-Ig
therapy was associated with improved infant survival (p =
0·0009).
Conclusions:
Treatment with high-dose IV-Ig during gestation appears to have
modified recurrent NH so that it was not lethal to the fetus or
newborn. These results further suggest an alloimmune mechanism
for recurrent NH.
Neonatal
hemochromatosis (NH) is a rare gestational condition in which
iron accumulates in the liver and extrahepatic sites of the
fetus in a distribution similar to that seen in hereditary
hemochromatosis. It is usually lethal to the fetus or neonate.
The risk of recurrence in subsequent offspring of a woman after
the index case is greater than 80 percent.
Dr. Whitington
has hypothesized that recurrent NH is an immune-mediated (alloimmune)
gestational disorder. Two research studies are in progress to study
the immune mechanism of NH.
Dr. Whitington designed
a treatment to prevent recurrent lethal NH, wherein women with a history
of having had their last pregnancy ending in documented NH were treated
with intravenous immunoglobulin derived from pooled serum of multiple
donors. All of the women treated on this protocol have given birth
to live babies with normal physical examinations and birth weights
that were appropriate for gestational age. Three-quarters of the babies
have shown evidence of being affected with NH (similar to the predicted
recurrence rate) and one-quarter have had liver injury severe enough
to require medical treatment. All babies have survived in good
health. These results strongly indicate that treatment with
high-dose IV-Ig during gestation modified recurrent NH so that it
was not lethal to the fetus or newborn. These results were published
in the November 6 2004 issue of the Lancet. (Whitington
PF, Hibbard JU. High dose immunoglobulin during pregnancy for
recurrent neonatal haemochromatosis. Lancet 2004;364:1690-8).
This treatment protocol is open to women who have had a baby affected
with NH and are pregnant or are anticipating pregnancy. Interested
persons should contact Dr. Whitington directly.
Dr. Whitington is
seeking to identify the target of the immune attack responsible for
NH. He is using serum collected from affected women as a source
of antibody to detect common fetal antigens that may be the antigen
in question. Preliminary results indicate that affected women’s
serum contains antibodies that detect a 32kd protein expressed in
fetal liver (both human and mouse) but not in mature liver.
If the results are confirmed, this fetal protein will be isolated
and purified and ultimately used to develop an assay (ELISA) for detecting
and quantifying antibody in the serum of women at risk. Being
able to measure antibody will permit refinement of the treatment protocol.
Affected women are invited to participate in these studies and should
contact Dr. Whitington if interested.
