Plain language summary
Antenatal immunoglobulin for fetal red blood cell alloimmunization
Pregnant women may develop antibodies in response to antigens on fetal red blood cells. The antibodies that result can cross the placenta to the fetus and break down red blood cells, leading to fetal anaemia. This has become less common with the routine use of anti D immunoglobulin in pregnant women with a Rhesus D-negative blood group and no pre-existing anti-D antibodies, but remains a cause of fetal death. Currently, standard management involves monitoring antibody titres in conjunction with ultrasound assessment of fetal well-being, and the use of intrauterine transfusion when fetal anaemia is diagnosed. Unfortunately, intrauterine transfusion poses significant risks because of its inherent invasiveness and procedure-related risks, including a risk of perinatal death.
Intravenous immunoglobulin has been proposed as an alternative form of treatment, with the advantage of being less invasive. There are no randomized trials of intravenous immunoglobulin given antenatally to women with severe fetal red blood cell alloimmunization to show if this offers any benefit over other forms of treatment or no treatment, but there are case series suggesting a possible role in delaying the onset of fetal anaemia requiring invasive intrauterine transfusion.
L'immunoglobuline prénatale pour l'allo-immunisation des globules rouges du fœtus
Les femmes enceintes sont susceptibles de développer des anticorps en réponse à des antigènes sur les globules rouges du fœtus. Ces anticorps peuvent traverser le placenta et détruire les globules rouges du fœtus, entraînant une anémie fœtale. Cela est devenu moins fréquent avec l'utilisation systématique de l'immunoglobuline anti-D chez les femmes enceintes de Rhésus D négatif et sans anticorps anti-D pré-existants, mais cela reste une cause de mort du fœtus. Actuellement, la prise en charge standard consiste à surveiller les titres d'anticorps en conjonction avec l'évaluation échographique du bien-être fœtal, et à recourir à la transfusion intra-utérine lorsqu'une anémie fœtale est diagnostiquée. Malheureusement, la transfusion intra-utérine présente des risques importants en raison de son caractère envahissant inhérent et de risques liés à la procédure, y compris le risque de mort périnatale.
L'immunoglobuline intraveineuse a été proposée comme alternative moins invasive de traitement. Il n'y a pas d'essais randomisés sur l'immunoglobuline intraveineuse administrée pendant la période prénatale aux femmes avec allo-immunisation grave des globules rouges du fœtus qui permettent de voir si cela présente un avantage par rapport aux autres formes de traitement ou à l'absence de traitement, mais il y a des séries de cas suggérant que cela pourrait retarder l'apparition de l'anémie fœtale nécessitant une transfusion intra-utérine invasive.
Notes de traduction
Traduit par: French Cochrane Centre 3rd June, 2013
Traduction financée par: Pour la France : Minist�re de la Sant�. Pour le Canada : Instituts de recherche en sant� du Canada, minist�re de la Sant� du Qu�bec, Fonds de recherche de Qu�bec-Sant� et Institut national d'excellence en sant� et en services sociaux.
Antigens on the red blood cell (erythrocyte) include the Rhesus antigens D, C, c, E, and e, as well as less common antigens such as Kell, MNS, and P antigens. Red blood cell alloimmunization has become less common with the routine use of anti D immunoglobulin during pregnancy and after delivery, but it may still occur with either D or non-D red blood cell antigens. Maternal antibodies may develop as a result of exposure to foreign red blood cell antigens via mechanisms including blood transfusion and transplacental fetomaternal haemorrhage. Since many of the red blood cell antigens are expressed on the fetal erythrocyte by the end of the first trimester, these maternal antibodies can cross the placenta. If they activate fetal red blood cell destruction (or, in the case of Kell antibodies, additionally suppress erythropoiesis), fetal anaemia can result, ultimately leading to hydrops or death, or both.
Traditionally, management of pregnant women demonstrating these antibodies has involved monitoring their antibody titres. In the past, once a titre reached a critical level, further evaluation via amniotic fluid bilirubin levels as an indirect measure of fetal haemolysis would be performed. Such evaluation is generally deemed mandatory when titres reach 32, as these levels correlate with a possibility of severe fetal anaemia in all antibody cases except Kell-alloimmunization. In the case of Kell-alloimmunization, antibodies not only activate fetal haemolysis, but also act independently to suppress erythropoiesis at the progenitor cell level, making the critical titre difficult to estimate (van Wamelen 2007). In the last decade, diagnosis of fetal anaemia via Doppler assessment of the fetal middle cerebral artery (MCA) peak systolic velocity has revolutionized practice in many centres, eliminating the need for amniotic fluid evaluation and thus rendering the management of alloimmunization far less invasive (Mari 2000; Oepkes 2006).
Despite the almost universal use of Doppler ultrasound in the evaluation of fetal red cell alloimmunization, the invasive requirement of the established therapy of choice, intrauterine transfusion (IUT), remains. Whilst experience in this field has improved greatly, complication rates are still impressive, with procedure-related perinatal mortality rates of up to 5% (van Kamp 2005).
Alternative treatment modalities have been proposed and trialled. These include plasmapheresis, oral erythrocyte membrane therapy, various medical agents such as azathioprine, promethazine and prednisolone, and intravenous immunoglobulin (IVIG) (Odendaal 1986; Ruma 2007). The latter has been used successfully in haematological and other obstetric settings, most notably and analogously in the area of platelet alloimmunization (Clark 1999; Rayment 2005). IVIG use was reported in isolated cases of red blood cell alloimmunization in the 1980s (e.g. Berlin 1985), and only began to be trialled more extensively in case series from 1990 onward (Chitkara 1990). As a proposed alternative treatment to IUT, IVIG is particularly attractive in the management of women with a history of severe alloimmunization in previous pregnancies. These women are at risk of alloimmunization and consequent fetal anaemia early in their subsequent pregnancy, when the technical difficulty and potential morbidity associated with IUT is at its highest. The use of IVIG instead of IUT, or to enable a delay in IUT, also reduces the risk of iatrogenic induction of maternal red cell alloimmunization (Watson 2006).
IVIG has proved safe in many applications, but is not free from adverse effects. Transmission of blood-borne diseases is now rare in most centres due to rigorous infectious control measures, but other serious reactions remain a real, if rare possibility. These include severe headaches, renal dysfunction, and maternal cardiovascular compromise (Cantu 1995; Duhem 1994).
There have been no randomized controlled trials comparing the use of IVIG either compared with no treatment or other treatments for fetal red blood cell alloimmunization. There have been 11 case series since 1990, with the majority (eight) examining the maternal administration of IVIG rather than fetal administration (Chitkara 1990; Connan 2009; Deka 1996; Dooren 1994; Fox 2008; Gottvall 1995; Kriplani 2007; Margulies 1991; Ruma 2007; Ulm 1999; Voto 1997). Ten of these studies concluded that IVIG offers benefit. The first (Chitkara 1990) reported a reduction in disease severity only in one case (involving anti-Kell antibodies), otherwise no benefit of IVIG was identified. Several authors (e.g. Gottvall 1995) have postulated that the reason for this lack of benefit was the lack of early commencement of therapy, suggesting the importance of commencing IVIG treatment before the onset of fetal anaemia.
The largest case series to date included 69 cases retrospectively, and concluded that adjuvant IVIG followed by IUT improved fetal outcomes (Voto 1997). The latest case series was reported in 2009 (Connan 2009), with all six women receiving IVIG as well as intrauterine and/or intraperitoneal transfusions. The use of these treatments in conjunction with serial Doppler ultrasound monitoring led to a delay in the onset of expected invasive therapy in five of the six women, as compared with poor outcomes in previous pregnancies. The majority (five) of women commenced IVIG in the second trimester.
All case series thus far have predominantly involved anti-D alloimmunization. Three studies included women with anti-Kell antibodies (Chitkara 1990; Connan 2009; Fox 2008); one also included a woman with anti-c antibodies as the causal factor for disease (Connan 2009). Based on current limited evidence, there appears to be a potential role for IVIG administration in the management of fetal red blood cell alloimmunization. However, there is a notable lack of comparative trials.
Description of the condition
Since the widespread introduction of routine anti D immunoglobulin prophylactic administration, the incidence of Rhesus D allommunization has decreased dramatically (from 43.3 per 1000 samples of women of reproductive age in the United States in 1967, to 2.6 per 1000 in 1996; Geifman-Holtzman 1997; Queenan 1969). Overall, 1.1% of women in one study from the United States were identified to carry an antibody previously reported to be associated with haemolytic disease of the fetus/newborn (Geifman-Holtzman 1997). When allommunization does occur, it can result in a very difficult disease to treat, often relying on the diagnosis of fetal anaemia and then usually serial invasive procedures to correct the anaemia in-utero. In the absence of treatment, this disease can lead to fetal death.
Current treatment involves IUT, which although potentially life-saving, unfortunately also involves intrinsic procedure-related risks including perinatal mortality.
Description of the intervention
The use of IVIG administered to the mother during the antenatal period.
How the intervention might work
The use of IVIG during the antenatal period may ameliorate the disease and allow later and less frequent red blood cell transfusions to the fetus, thus reducing the invasive procedure-related risk to the pregnancy.
Postulated mechanisms for the efficacy of IVIG in this area include the inhibition of transplacental passage of red blood cell antibodies, and/or a direct Fc blockade of the fetal reticuloendothelial system, thus reducing the degree of fetal phagocytosis of sensitised fetal red blood cells (Clark 1999). Some authors have also suggested that IVIG can downregulate the maternal immune response, for example by increasing suppressor T cell function, thereby inhibiting antibody synthesis (Berlin 1985; Porter 1997). Additionally, IVIG may bind maternal antibodies or enhance their dissociation from antigenic components, decreasing their destructive effects (Ballow 1991).
Why it is important to do this review
A systematic review of the available literature is needed to establish if there is sufficient evidence to establish that IVIG for severe red cell alloimmunization is an efficacious treatment which should be recommended for women with this disease or, if not, to dissuade clinicians from continuing with its use.
To systematically review the available evidence on the efficacy and safety of the use of intravenous immunoglobulin (IVIG) antenatally to women with severe fetal red blood cell alloimmunization.
Criteria for considering studies for this review
Types of studies
Randomized controlled trials and quasi-randomized controlled trials, with parallel study design. Trials with cross-over study design will not be included. If cluster-randomized trials are available, these will also be included. Trials that are published only in abstract form will only be included if the authors are contactable for further details.
Types of participants
Women with red blood cell group antibodies and fetuses at risk of alloimmunization, as defined by past perinatal death secondary to fetal alloimmunization and/or early requirement for intrauterine transfusion (IUT) in previous pregnancies (at less than 20 weeks' gestation).
Types of interventions
IVIG(at any dose, frequency or duration) versus no therapy
IVIG (at any dose, frequency or duration) versus plasmapheresis (using any regimen)
IVIG (at any dose, frequency or duration) versus phenobarbital (at any dose, frequency or duration)
IVIG (at any dose, frequency or duration) versus any other therapy
Types of outcome measures
These outcome measures will be applied to all the comparisons, if the trial data allow it.
Fetal anaemia as diagnosed via cardiotocography (CTG), middle cerebral artery (MCA) Doppler assessment, amniocentesis, fetal blood sampling, or hydrops on ultrasound
Gestation at first transfusion
Gestation at delivery
Haemoglobin at delivery
Admissions to neonatal intensive care unit (NICU) or special care nursery (SCN), and length of stay
Treatment after delivery - phototherapy, exchange transfusions, top-ups, IVIG
Peak serum bilirubin (corresponding to age in hours)
Complications of treatment
Search methods for identification of studies
We searched the Cochrane Pregnancy and Childbirth Group’s Trials Register by contacting the Trials Search Co-ordinator (19 December 2012).
The Cochrane Pregnancy and Childbirth Group’s Trials Register is maintained by the Trials Search Co-ordinator and contains trials identified from:
monthly searches of the Cochrane Central Register of Controlled Trials (CENTRAL);
weekly searches of MEDLINE;
weekly searches of EMBASE;
handsearches of 30 journals and the proceedings of major conferences;
weekly current awareness alerts for a further 44 journals plus monthly BioMed Central email alerts.
Details of the search strategies for CENTRAL, MEDLINE and EMBASE, the list of handsearched journals and conference proceedings, and the list of journals reviewed via the current awareness service can be found in the ‘Specialized Register’ section within the editorial information about the Cochrane Pregnancy and Childbirth Group.
Trials identified through the searching activities described above are each assigned to a review topic (or topics). The Trials Search Co-ordinator searches the register for each review using the topic list rather than keywords.
Searching other resources
We planned to search reference lists of retrieved articles.
We did not apply any language restrictions.
Data collection and analysis
Methods of data collection and analysis to be used in future updates of this review are provided in Appendix 1.
Description of studies
Results of the search
No trials were found.
Risk of bias in included studies
There are no included studies.
Effects of interventions
There are no included studies.
There are no randomized controlled trials examining the administration of immunoglobulin antenatally to prevent complications of red blood cell alloimmunization, although there are some data from case series to suggest its potential benefit. Ten of the 11 case series that have been reported since 1990 produced promising results, with a reduction in disease severity and/or improvement in fetal outcomes. The latest of these series was reported in 2009, with a delay in the onset of expected invasive therapy in five of six patients.
This review demonstrates the continued reliance on case series and first principles in the management of severe fetal red blood cell alloimmunization during pregnancy.
As part of the pre-publication editorial process, this review has been commented on by three peers (an editor and two referees who are external to the editorial team) and the Group's Statistical Adviser.
The National Institute for Health Research (NIHR) is the largest single funder of the Cochrane Pregnancy and Childbirth Group. The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the NIHR, NHS or the Department of Health.
Contributions of authors
This review was drafted by Kae Sheen Wong with input from Kirsten Connan, Shelley Rowlands, Louise Kornman, and Helen Savoia.
Declarations of interest
None known for Kae Sheen Wong.
Dr Kirsten Connan was the principal author for the paper "IVIG - is it the answer? Maternal administration of immunoglobulin for severe fetal red blood cell alloimmunization during pregnancy: A case series". This article has been accepted for publication with the Australian and New Zealand Journal of Obstetrics and Gynaecology. Three other review authors (Shelley Rowlands, Louise H Kornman and Helen F Savoia) were also co-authors on the same paper.
Dr Helen Savoia has, in the past eight years, and is currently employed on a casual basis by Australian Red Cross Blood Service (ARCBS) for the provision of transfusion medicine advice. ARCBS is the sole provider of fresh blood products in Australia and provides plasma to CSL Bioplasma for the manufacture of intravenous immunoglobulin.