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ARTICLE |
Department of Pediatrics, Northwestern University Feinberg School of Medicine, Children's Memorial Hospital, Chicago, Illinois
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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METHODS. Women with a history of pregnancy ending in documented neonatal hemochromatosis were treated with intravenous immunoglobulin at 1 g/kg of body weight weekly from week 18 until the end of gestation. Extensive data were prospectively collected regarding the gestational histories of the subjects. The outcomes of treated pregnancies were compared with those of previous affected pregnancies, which were used as historical controls.
RESULTS. Forty-eight women were enrolled to be treated during 53 pregnancies. The gestational histories of these women demonstrated the high risk of occurrence of neonatal hemochromatosis: 92% of pregnancies at risk resulted in intrauterine fetal demise, neonatal death, or liver failure necessitating transplant. In contrast, with gestational therapy, the 53 at-risk gestations resulted in 3 failures and 52 infants who survived intact with medical therapy alone. When compared on a per-woman or per-infant basis, the outcome of gestation at risk for neonatal hemochromatosis was improved by gestational therapy.
CONCLUSIONS. Neonatal hemochromatosis seems to be the result of a gestational alloimmune disease, and occurrence of severe neonatal hemochromatosis in at-risk pregnancies can be significantly reduced by treatment with high-dose intravenous immunoglobulin during gestation.
Key Words: fetal mortality • intravenous immunoglobulin • iron overload • maternal antibodies • neonatal death
Abbreviations: NH—neonatal hemochromatosis • IVIg—intravenous immunoglobulin • Ig—immunoglobulin • AFP—
-fetoprotein • INR—international normalized ratio • IUFD—intrauterine fetal demise
Neonatal hemochromatosis (NH) is clinically defined as severe neonatal liver disease in association with siderosis of tissues outside of the liver.1–4 It seems to be a gestational disease in which fetal liver injury leads to the NH phenotype in the neonate, in which cirrhosis and liver failure are common features.4–6 Repeated occurrence in the offspring of women who have had 1 affected infant is a notable feature of NH. This apparent rate of occurrence of severe disease in siblings after the index case is 60% to 80%.7,8 Counseling regarding future pregnancy has been determined by this high risk, with avoidance being often advised.9
We have proposed that NH is often the result of maternal alloimmunity directed against the fetal liver.4,10 Based on the alloimmune concept, we have applied intravenous immunoglobulin (IVIg) therapy in an attempt to prevent recurrent severe NH. This approach has been used to modify the severity of other gestational alloimmune diseases.11 The early results of this preventative therapy involving the birth of 15 infants reported in 2004 demonstrated a significant improvement in infant survival.8 The current work provides the results after 48 women were enrolled for 53 treatment episodes. The background data collected during this study constitute the largest reported series of NH and show several features of the disease that support the concept that NH is often the result of alloimmunity. The improved outcome with gestational therapy designed to limit the severity of gestational alloimmune disease demonstrates that recurrence of severe NH in pregnancies at risk is in large measure preventable.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Design and Procedures
The treatment consisted of IVIg administered weekly at a dose of 1 g/kg of body weight beginning on the 18th week of gestation. Various standard commercial preparations of IVIg were used depending on local availability. The patient's obstetrician administered IVIg in an outpatient setting, wherein the patient was under close observation, or, in the United States, it was administered in a few cases by home-infusion companies with appropriate expertise. Before beginning treatment, every participant was tested for IgA deficiency, which is a risk factor for anaphylaxis with IVIg.12 The progress of pregnancy was monitored routinely.
Newborn infants were examined by a qualified pediatrician paying particular attention to signs of liver disease. Laboratory tests were performed on the first day of life to detect liver dysfunction and liver involvement with NH: serum -fetoprotein (AFP) and ferritin are considered sensitive for detecting NH, although they are not specific, whereas the international normalized ratio (INR) is a measure of liver synthetic function.13–15 These tests were performed in the clinical laboratories of the local institutions. Values that were considered abnormal (outside of acceptable normal values for newborns) used in this analysis were as follows: serum AFP for term neonates >84000 ng/mL and for 32 weeks of gestation >200000 ng/mL16,17; serum ferritin >800 ng/mL18; and INR >2.0. Infants with significant clinical liver dysfunction were treated with a cocktail of antioxidants and chelating agents as described.8,15,19
Statistical Analysis
Intent-to-treat analysis was applied in which the outcomes of all of the gestations in which IVIg therapy was initiated were analyzed. The null hypothesis to be tested was "administration of IVIg during gestation in women at high risk for occurrence of NH does not improve infant outcome." Previous affected gestations were used as historical controls. The outcome of gestation was either good (survived with medical treatment alone) or poor (fetal or neonatal death or required liver transplantation). Gestations that ended earlier than 18 weeks were excluded from the analysis, because IVIg therapy in this protocol would have had no effect.
Two approaches to statistical analysis were used. McNemar's test was applied to assess on a per-mother basis the effect of gestational treatment on outcome. One previous affected gestation was selected for each woman by random-number generation, and the outcome of that gestation was compared with the outcome of the treated gestation. Five women were each treated through 2 gestations; the outcome of the first (closer to untreated gestations) was used in this analysis. 
2 test was used to assess outcome on a per-gestation basis. The outcomes of infants from all of the untreated affected gestations were compared with the outcomes from treated gestations. SPSS statistical software (SPSS Inc, Chicago, IL) was used for both analyses.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Outcome of Untreated Gestations
The gestational histories of the 48 participants are given in Table 1 and Fig 1. Of 141 pregnancies, 111 ended after 18 weeks of gestation: 96 with live births and 15 with intrauterine fetal demise (IUFD). Eighteen women suffered 30 fetal losses at 
18 weeks, which consisted of 5 elective abortions, 1 medical abortion, and 24 spontaneous miscarriages (3 for each of 3 women). All of these fetal losses occurred before the index case of NH, although half of the spontaneous miscarriages occurred from 14 to 18 weeks' gestation and in continuity with the cases of NH in the sibships, and, thus, may represent cases of NH causing fetal death before 18 weeks' gestation. Of the 15 IUFDs at 
18 weeks, 13 had proven NH, and the other 2 were assumed to, because they followed or were in sequence with a proven case. Of 97 live-born infants (including 1 set of twins), 44 were healthy apparently unaffected infants, all but 2 preceding the NH index case in the sibship, and 53 were affected with NH. Of affected infants, 36 died without liver transplantation (22 having received chelation-antioxidant therapy); 6 survived without liver transplantation (3 with and 3 without antioxidant-chelation therapy); and 11 received liver transplants, of whom 4 survived. The mortality rate of affected live-born infants was 81%, and 89% either died or required liver transplant. The outcome of affected untreated gestations was poor: 92% resulted in IUFD, neonatal death, or liver failure necessitating transplant. Thirteen women had a total of 21 (1–3 each) untreated gestations after the first affected with NH: only 2 were unaffected (the only "skipped" gestations in our series). This provides an apparent recurrence rate of 90% in this series (19 occurrences of 21 possible gestations) without gestational therapy.
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Complications of Gestational IVIg Therapy
The only major complication of therapy was the development of aseptic meningitis in 1 subject after having received 1 dose of IVIg. She withdrew from further treatment, and follow-up is unavailable other than that she recovered from the aseptic meningitis without consequence. Several women reported minor difficulty that was thought to be because of the treatment: headaches after infusion (n = 2), urticaria or itching during infusion (n = 2), nausea (n = 1), myalgia and malaise (n = 1), and chest pain (n = 1). Symptoms responded to lowering of the infusion rate during subsequent treatment sessions or dividing the weekly dose into 2 infusions. Two women developed complications of pregnancy not thought to be the result of treatment: hypothyroidism (n = 1) and thrombocytopenia (n = 1).
Health and Outcome of Infants Born After Gestational Therapy
No intrauterine growth restriction, fetal liver disease, or other evidence of fetal distress was detected in any case other than the infant born at 26 weeks. Two infants had associated oligohydramnios determined by prenatal ultrasound. All of the infants survived with medical support alone. No infant had overt liver failure. Six had initial INR values >2.0 but were otherwise clinically stable. Twenty-nine infants (including the 6 with elevated INR) had elevated serum AFP and/or ferritin levels, suggesting that they may have had some liver involvement with NH. In total, 70% (29 of 41) of the infants with both serum ferritin and AFP measured showed suggestive evidence of being affected with NH.
The treatment of the infants born with gestational IVIg is shown in Table 1. Nine infants received therapy with the cocktail of chelation agents and antioxidants for indications of prolonged INR or other clinical findings of concern to their caretakers. An additional 15 were prescribed vitamin E alone for various indications, including abnormal serum biochemistry values. Local pediatricians provided follow-up data from the time of birth (dates of birth: February 1998 to September 2007) until the present. All of the infants survived with no evidence of liver disease. One child developed type 1 diabetes at 4 years old.
Statistical Analysis of Effect of IVIg Therapy on Outcome of Gestation
The outcomes of the gestations with IVIg treatment (n = 48) were compared with those of previous affected gestations paired on a per-mother basis. Of the 48 treated mothers' previous affected gestations selected randomly, 2 had good outcome (survived with medical therapy), and 46 had poor outcome (fetal or neonatal death or liver failure necessitating liver transplantation), whereas the outcomes of treated gestations were 45 good and 3 poor (2 fetal or neonatal deaths and 1 withdrawal). IVIg therapy during gestation was associated with a significantly improved outcome (McNemar's test P <.0001). Outcomes of infants from untreated gestations including and after the index cases (n = 70) were compared with infants from treated gestations (n = 55; Table 2). Outcome of infants from gestations affected by NH or at risk of being affected was improved by gestational therapy (2 test P < .0001).
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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The women who participated in this study resided in 9 countries on 5 continents. Although the majority was from the United States, this broad sampling provides a unique prospectively collected data set that demonstrates, among other things, that NH seems to affect all populations. No participants were treated in east Asia or Africa. This may be because of relatively limited access of very sick newborns to NICUs where they might have been diagnosed and perhaps limited use of postmortem examination to diagnose disease causing fetal or neonatal demise. It might also be because of reluctance to participate in the treatment protocol because of cost and/or access to the large quantities of IVIg required. Two of the participants were of African descent and 1 was east Asian, suggesting that race itself does not affect the racial distribution of the study cohort.
A high rate of occurrence of NH in the offspring of women who have had 1 affected infant has been known for some time. This observation has fueled efforts to find a gene defect responsible for NH, which have been unsuccessful. In the most important study of this type, investigators from the United Kingdom examined a large number of affected families and concluded that NH is a genetic disease despite not being able to find a responsible gene.7 The apparent recurrence rate (the rate of occurrence of NH in pregnancies subsequent to the index case) in that study was 67%, whereas our data show a 90% rate of occurrence of NH in pregnancies at risk. This high rate of recurrence effectively excludes mendelian genetic inheritance. Furthermore, it has been observed that several woman have given birth to affected infants with different male parentage, but not vice versa, and that no female siblings of women having an infant with NH have themselves had an affected infant.4,7 This pattern is very difficult to explain on the basis of a genetic disease. Nevertheless, many families who have had an infant affected by NH are referred for genetic counseling, and in our experience geneticists and genetic counselors generally believe that NH has a genetic basis. Many believe that NH is part of the hereditary hemochromatosis family of diseases, which it clearly is not,3,20 and that it is inherited in an autosomal recessive manner, which of course reduces the expected recurrence rate several fold. This pervasive belief has interfered substantially with the access of families to gestational treatment and should be eliminated in the face of overwhelming evidence to the contrary.
The data also provide a reasonably unbiased estimate of the lethality of NH. Recent single-center reports from very good and highly experienced transplant centers have shown that NH is variably although generally poorly responsive to medical therapy and that transplantation may offer the best hope for survival.21–23 In these series the rate of survival with application of the chelation-antioxidant mixture of medical therapy and without liver transplantation varied from 10% (1 of 10)22 to 50% (3 of 6),21 and the overall survival of infants with NH, including those receiving liver transplants, was 50% to 69%.21–23 It should be recognized that these rates of survival represent small, select, and biased samples in that they were achieved in infants healthy enough to survive referral and transport to major transplant centers. They are in stark contrast to the overall survival rate of 19% in this series presenting in diverse medical centers in medically developed countries. Eleven of the 53 infants with NH underwent liver transplant, with 4 surviving. Although there is no question about the potential value of liver transplant therapy in this setting, the specialized experience required to achieve good outcomes may curtail its use and limit its value in the management of NH overall.24 Only 11% of affected infants survived without liver transplant, which is in general agreement with other published data.14,15,19,21–23
The approach to medical treatment of newborns with NH remains somewhat controversial, in particular, the use of the chelation-antioxidant mixture.25 Chelation-antioxidant therapy was first implemented at a time when iron-related oxidant injury was considered to be a major cause of organ damage in NH.26 Current evidence suggests that iron deposition may be a secondary phenomenon and minimally involved in the mechanism of organ injury.3,4 In the current series, only 6 infants with severe NH survived without liver transplant: 3 received the therapy and 3 did not. These limited data combined with published data14,15,19,21–23 further suggest that chelation-antioxidant therapy may have limited value in treating severe NH. Recently, the growing evidence that NH is an alloimmune disease has led to an alternate approach to treating affected newborns.4,27,28 This approach involves the application of exchange transfusion to remove reactive antibodies, followed by administration of IVIg to restore broad humoral immunity. Although the initial experience has shown promise, it remains to be seen through more extensive application whether this approach can improve survival of severely affected newborns.29
In contrast to the response to medical therapy, a fatal course of NH seems to be preventable by gestational therapy aimed at limiting fetal injury because of maternal humoral alloimmunity. Treatment with exogenous pooled adult IgG is thought to alter the natural course of gestational alloimmune disease by 3 mechanisms: by blunting the maternal immune response to fetal antigens; by flooding the placental IgG transport mechanism with nonspecific antibodies; and by nonspecific antibody binding that limits the binding of reactive alloantibodies to target antigens.11 Our results show that this treatment dramatically improves the outcome of pregnancy in women at risk. Indeed, the results in this disease are far better than those recorded in the other 2 gestational alloimmune diseases in which it has been extensively used: erythroblastosis fetalis because of Rh incompatibility and alloimmune thrombocytopenia. Why this is so is unclear. It may be because of the large mass of the liver and subsequent requirement for large amounts of specific immunoreactive IgG to traverse the placenta to produce global liver injury. Blocking only a fraction of the flux of reactive IgG to the fetus might be enough to limit injury to a degree that the liver survives intact.
In addition to the concerns expressed previously about the general application of this treatment strategy, including its expense and the fact that some women may be needlessly treated,8 this extended series demonstrates that it may not be 100% effective in preventing recurrent severe disease. Two infants were lost after the mothers began therapy. Although neither can be said to have resulted from NH-related alloimmunity, the apparent rate of loss (2 of 48 women starting treatment) is somewhat greater than the stated rate of fetal loss in the second half of pregnancy, commonly estimated to be 1 in 150 pregnancies in developed countries. In addition, 1 woman withdrew from therapy because of a complication. Despite these failures, this therapy is highly effective in preventing severe NH. Two reports involving 3 cases not included in this study show that it has been accepted in clinical practice.30,31 It seems, therefore, that this therapy should be recommended as appropriate clinical care for pregnancies at risk for NH pending evidence from other investigators to the contrary.
A design flaw in this study stems from the fact that women were enrolled because their previous gestation was affected in lieu of having some specific marker that would provide unequivocal evidence that the current one would be. This approach is justified because of the high risk for occurrence of highly lethal disease. It is also made palatable by the observation that the majority of infants born after gestational therapy showed some evidence of being affected with NH. It is impossible to know whether the affected infants would have been severely affected or whether the apparently unaffected infants would have been affected but for the treatment. Our laboratory effort is focused on developing that unequivocal marker of disease needed to remedy this flaw. However, at present, we must live with the possibility that some women may be receiving therapy without need. Another design flaw is failure to randomize therapy. This simply cannot be done, because NH is a rare disease presenting in disperse medical situations, because there is no other reasonable therapy against which to compare effect, and because the consequences of failure are too great. Despite these design flaws, the results provide an overwhelming endorsement for using IVIg during gestation to prevent severe NH in infants of women at risk.
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CONCLUSIONS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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ACKNOWLEDGMENTS |
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Judith U. Hibbard, MD, coauthor of the publication that reported the first 15 infants born after gestational therapy, reviewed this publication and provided constructive critique.
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FOOTNOTES |
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Address correspondence to Peter F. Whitington, MD, Children's Memorial Hospital, Mail Box 57, 2300 Children's Plaza, Chicago, IL 60614. E-mail: p-whitington{at}northestern.edu
The authors have indicated they have no financial relationships relevant to this article to disclose.
| What's Known on This Subject The high rate of recurrence of NH in offspring of women who have had one affected baby suggests a gestational alloimmune mechanism. Gestational treatment with IVIG is potentially useful to prevent severe disease in subsequent offspring of women at risk.
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| What This Study Adds This large prospectively acquired cohort demonstrates a rate of recurrence even higher than previously estimated and a very poor prognosis for babies with NH. Gestational treatment with IVIG is highly effective in reducing the rate of recurrence and improving prognosis.
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REFERENCES |
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