Research Articles:
Note: All articles are copyright of their respective owners
Search the US National Institute of of Health's website for latest Neonatal Alloimmune Thromboctyopenia articles by following this link:
www.PubMed.gov.
Here are a select few NAIT research articles, but we have many more we have purchased over the years, please
contact us if you are looking for any specific research and we would be happy to try to help.
Fetal and Neonatal Alloimmune Thrombocytopenia: A Management Algorithm Based on Risk Stratification, Obstet Gynecol, 2011 Nov;118(5):1157-1163.
This is an update from the one onging US "study" as reported by Pacheco LD, Berkowitz RL, Moise KJ Jr, Bussel JB, McFarland JG, and Saade GR this time. We purchased this article as it does offer some insight to what many of us have been witnessing the past couple years, which is the Blood Center of Wisconsin seeming to diagnose more inconclusive NAIT cases when anti-platelet alloantibodies are not detected, and then sometimes recommending not to treat in the next pregnancy until they are detected. This seems to add a good deal of risk, in my opinion, unless these antibody tests are highly acurrate, and there is some indication in other research articles that they are not. This article's "algorithm", if it can be called that, shockingly leaves room for two NAIT parents who are tested to be 100% incompatible for HPA-1, the most commonly associated antigen for NAIT in the US, and had a child die from an ICH, would recommend antibody testing at 12 weeks and NOT TREATING if no antibodies were detected and then waiting a FULL THREE MONTHS to test again at 24 weeks. So if they are testing again at 24 weeks, they must think the 12 week test may fail to detect antibodies, otherwise why run the test? They also are on record saying that treatment should begin at 12 weeks with a prior ICH, but if there were a prior ICH with no antibodies detected until 24 weeks of the next pregnancy, by their own writings, they would be treating a full three months later than they reocmmend.
Here is an exerpt from the article defining this new "algorithm's" first group:
"STRATUM 1
History of previous fetus or newborn with thrombocytopenia or intracranial hemorrhage of unknown etiology. Paternal incompatibility for human platelet antigens may be documented, but specific anti-HPAantibody is not present. These patients cannot be classified as having fetal and neonatal alloimmune thrombocytopenia but have the potential to develop specific antiplatelet antibodies not previously detected as the pregnancy progresses. These women do not require empiric therapy early in the pregnancy, but we believe should be followed with maternal anti-HPA antibody screening (testing against
panel platelets expressing HPA antigens implicated in cases of alloimmune thrombocytopenia like HPA 1–6,9,15) and cross matching with paternal platelets at 12, 24, and 32 weeks of gestation."
There is little or no data associated with the results of this latest experiment by this group of doctors. I can only hope it turns out better than their Fetal Blood Sampling (FBS/PUBS) expirements or their late treatment starts.
The good news is that this group seems more comfortable in their writings in using a non-invasive approach and avoiding FBS/PUBS, writing:
"FETAL BLOOD SAMPLING
Fetal blood sampling has traditionally been included in the management of alloimmune thrombocytopenia to evaluate the response to therapy and identify those fetuses that might benefit from more intense treatment. 7 Unfortunately, serious complications during fetal blood sampling in the setting of alloimmune thrombocytopenia have been reported in 0–8% of the cases.8,9,12,15 We therefore propose early empiric implementation of optimized therapy according to risk of recurrence based on severity stratification as opposed to undertaking fetal blood sampling to identify which patients need additional therapy."
Interstingly they never refer to the overal risk they added to their studies using FBS, and more so refer to the 0-8% risk per FBS. E.g., in their 2002 report at the Boston Park Plaza Hotel, they reported, "Overall, in these studies, 6 patients had ICH (74 pregnancies); 211 FBS procedures in 91 patients were complicated by 3 fetal deaths, and 14 deliveries precipitated by FBS, among other complications." So 17 out of 211 is 8% having either died or premature birth per FBS, but if you divide instead by 91 patients, you get over 18% of the patients either had their baby die or born prematurely due to FBS/PUBS, not even including the "among other complications" part. Why rehash all of that? Because results matter, and if their reasoning that FBS helped NAIT treatment was flawed, shouldn't doctors and parents be wary of this latest recommendation that seemingly adds risk to the treatment equation with little supportive data?
I feel that parents should be provided the information and allowed to treat in a manner that they feel most comfortable with. If they want to wait and treat until antibodies are detected, that is their choice as should be if they prefer to treat in the absence of antibodies being detected as long as they have a clear antigenic mismatch between the baby and the mother and a prior child that was severely thrombocytopenic with no other cause determined. Also, if parents perfer to have antibody tests more frequently than every three months, they should be allowed as waiting three months seems much too long given the severity of NAIT.
As always, we welcome your input and are happy to share more of this article or arm you with it if you are encountering questions about it with your doctor. Please contact us.
While we had 100% chance of NAIT recurrence, we purchased this article hoping to help those of you who are in the 50% group where the father is heterozygous. We are happy to report that these doctors have developed a non-invasive test to determine if the baby carries the HPA-1a gentotype, and would thus be at risk for NAIT. We are not sure how quickly the availability of this test will spread around the world, but since amniocentesis carries a very small risk of miscarriage and also the indirect risk of increasing maternal immune sensitization against the baby by exposing the mother to the baby's foreign platelet proteins, we see this a wonderful development. We congratulate and thank Scheffer, Ait Soussan, et. al., for developing this new tool for NAIT parents in the HPA-1 heterozygous group (which this article reports to be about 30% of the HPA-1 cases.) I contacted the director at the Blood Center of Wisconsin to see when this test might be available, but they reported that due to patent protection, they were not using it presently, but monitoring it for when it might be affordably available. It may be availble elsewhere, so it seems worth having your doctor investigate it. If anyone hears any labs offereing this, please let us know and we will post them along with share them with the many we know n the 50% group.
This article includes research by Cécile Kaplan in France, who has published on NAIT for many years, along with others, and seem to be yet another of the old guard coming into line with the reality that non-invasive treatment is just as effective (and avoids the risks of the invasive procedures), plus of note in their conclusion they state, "This observation suggests also to start IVIG early during pregnancy and to continue treatment up to delivery." We have long promoted early and non-invasive NAIT treatment, and are pleased that "old school" doctors seem to finally be moving in a more cautious direction. The article concludes with:
Conclusion. This study confirmed that maternal therapy with intravenous immunoglobulin for fetal alloimmune thrombocytopenia gives satisfactory results. It also showed that a less invasive approach, especially a reduction in the number of fetal blood samples, is possible without deleterious consequences. This observation suggests also to start IVIG early during pregnancy and to continue treatment up to delivery.
We still have a ways to go in educating doctors and changing the ways of some prominent doctors in the US seemingly clinging to their old protocols that still include invasive procedures and late treatment starts (and also outcomes that include ICHs or severely thromboctyopenic counts.) Over the years a couple of NAIT parents have taken the time to email us that we were wrong to promote early non-invasive treatment as a better approach, even though our doctor, the late Dr. Alan Beer said it was a better way to treat NAIT (whom many consider the leading Reproductive Immunologist of his time) and he had achieved 100% success using it. One patient of Dr. Bussel and Dr. Berkowitz even emailed me that it was immoral for me to say one doctor's approach was better than another, (despite the compelling science.) Turns out we found it would probably be immoral to not say what we felt and knew to be true. A good number of publications in the last three years, including this one, have clearly indicated that our past critical view of the high percentage of serious complications associated with FBS/PUBS and recommending a non-invasive approach (as advocated by Dr. Beer, Dr. Kwak-Kim and others,) has been vindicated. For anyone with a calculator this debate should have been over a decade ago, yet it still persists with some. The data is also compelling that early treatment can achieve better results. For those old PUBS fans who took issue with our non-invasive treatment stance, we do accept apologies :-) In all seriousness, we understand parent's appreciation for their doctors and realize only the smaller percentage of parents who encounter the issues know any better, but our goal is to help inform NAIT parents of what we understand to be the best treatments available to help avoid severely thrombocytopenic counts (and consequently ICHs) and any complications that could harm the baby.
This article gives a nice retrospective look at the Bussel, Berkowitz, et. al., and some select other researcher's data and approaches and again states that currently non-invasive treatment approaches are recommended. Notably, it is also the first time we have finally seen Dr. Bussel mention the risks of increased maternal sensitization that can be caused by FBS. The full text article is available online at time of typing this, so follow the above link and present it to your doctor if they are recommending a FBS/PUBS. This article also helps show the success and failure rates for the corresponding studies, showing about 3% risk of an ICH in treated cases and about 80% achieving counts birth counts above 50k, which is encouraging. Dr. Beer felt he could achieve a count above 50k nearly 100% of the time by treating earlier in the pregnancy, but ultimately if 100% of the bleeds could be avoided, that would be a wonderful statistic. We still favor striving for higher birth counts as we feel it can reduce the risk of a bleed, plus it can avoid the need for NICU time, and transfusions and IVIG in the newborn. Why not strive to achieve this in the other 20% of the cases, which is one out of five NAIT pregnancies? Cost may be one reason, but NICU time is not cheap either. The argument we have heard is that if they treat all early, then they are overtreating/overspending in many of the cases. That is why the use of non-invasive tests could be of benefit to help show which pregnancies need more IVIG and which ones do not. Dr. Kwak-Kim feels her tests can accomplish this.
Bertrand, Drame, Martageix and Kaplan's article points out three very important things that we have been trying to tell others about for many years:
1. Use a non-invasive approach
2. IVIG + steriods can achieve higher birth counts than just one of those drugs alone
3. Non-invasive tests can have signifcance and help guage treatment's effectiveness, with the article stating, "The maternal alloantibody concentration during pregnancy is predictive of fetal thrombocytopenia and is a prognostic factor for therapy response."
There have been other articles written showing that maternal antibody titer can be used somewhat to predict severity around 75% of the time, but other researchers like Dr. Bussel deemed there was no reliable non-invasive test as recently as 2009. This article may change his mind or at least open it to investigating it more. The article states"
"In this study we confirm that a high maternal alloantibody concentration measured before 28wg and before any treatment is correlated with a severe fetal thrombocytopenia.12 We refined the antibody concentration threshold, now corresponding to 28 IU/mL. This threshold allows improvement in the sensitivity (81.2%) and the specificity (91.7%) of the testing, with high positive and negative predictive values (respectively 92.3% and 79.9%) (Table 3). Under
the threshold of 28 IU/mL, the antibody concentration cannot be considered as a predictive parameter of the fetal status.
This maternal parameter allows recognition of high-risk fetuses and the need for therapy."
Dr. Kwak-Kim had told us the antibody titer has significance, but that she also looks for the changes in it and other immune testing to help indicate how well treatment was working. The Blood article possibly supports that by stating:
"The pattern of the antibody concentration follow-up was variable: steadily low antibody concentration (<28 IU/mL); decreasing towards delivery or increasing during the second or third trimester of pregnancy or just after delivery."
Dr. Kwak-Kim also looks at the TH1/TH2 cytokine ratio as there is research that indicates a shift in this ratio can give an indication that the immune response is increasing and this activity could precede the increase in antibody production. We would like to see a study of the TH1/TH2 ratios and how they correspond to platelet counts, and possibly someday we will see it or some other biological marker use to more effectively manage NAIT treatment.
This is another article by the Bussel, Berkowitz, McFarland, et. al., group that helps illustrate how they use a different measurement for success than Laura, myself and hopefully the doctors who treated us or are treating you. Please read the summary and make up your own mind:
"RESULTS: Five of 37 fetuses suffered ICHs. Two ICHs had platelet counts >100,000/mL, and 1 was grade I. The other 2 ICHs were unequivocal treatment failures; both were grade III-IV and resulted in fetal demise. CONCLUSION: These findings demonstrate the success of stratified treatment in these HR patients, which tailored interventions according to the timing of the sibling's ICH."
In my opinion, this spiltting of hairs on the timing of the previous child's ICH proves little, is not completely sound from an immunological standpoint, and the results are certainly not what I would call a "success" with five of 37 having an ICH. Statitistics was my technical elective when studying Engineering at the University of Illinois, and quite frankly, a sample size of 37 is quite small to really predict represenative outcomes in a larger scale. Speaking as a parent, zero ICHs out of the 37 would be reason to call it a "success of stratified treatment". Also, I think most parents would consider a Grade I ICH a treatment failure, too, but clearly it is much better than death. If you wonder why we were drawn to the late Dr. Beer's stated treatment protocol goal to achieve a birth count above 50,000 in 100% of treated cases, which is above what is considered severe thrombocytopenia, I think the above groups protocol that includes deaths in what they define as succes stands in stark contrast. They may be right that if we treated in a way to avoid all the bleeds and achieve higher counts, we might over-use IVIG in some cases. My point is so what? Isn't it better than running the risk of some babies dying? If you feel as we do, I suggest you follow Dr. Beer's advice and accept no lesser protocol than his. I know of no NAIT parents who regret making that choice, and only one who had a birth count below 50k. It was 42k, but delivery was scheduled later than Dr. Kwak-Kim recommended. We have purchased this article for our library, so please
contact us if you would like more information in this article.
This summary compares three treatment protocols used on 98 pregnancies with no ICHs and only one death related to a FBS (Fetal Blood Sampling) procedure.
This is the first publication we have seen that finally seemed to state what has seemed obvious to us and others for years with the Berkowitz, Bussel, etal, data related to PUBS/FBS, and it appears this group's writings changed to say to avoid PUBS, possibly motivated by seeing this in writing:
“In conclusion, the studies by Birchall et al. and Berkowitz et al. describe a considerable number of complications and adverse outcomes associated with FBS. However, such risks could be acceptable if the invasive management would result in a better overall outcome when compared with a completely noninvasive approach. This, as our data suggest, does not seem to be the case.”
This article also is the first we have seen that mentions the risk of FBS/PUBS increasing the maternal immune response that Dr. Kwak-Kim warned of almost a decade ago in our consultation with her when asking about the use of PUBS that we had seen in others' writings. The article states (bold added for emphasis only):
“Controversy exists whether FBS, with its inherent risks of bleeding, boosting of antibody levels, emergency (preterm) caesarean section and fetal loss, should remain part of the management of FNAIT.” The full text of this article is availble through the above link.
This is the full text of a large Norwegian study of more than 100,000 pregnancies, that sheds some light that the initial NAIT maternal sensitization may not occur in the first pregnancy as much as once thought and that delivery or a previous miscarriage/sponstaneous abortion may cause it more than previously thought. It also cites the articles that link higher antibody counts to severe thrombocytopenia and seems to concur with that thought, despite Bussel and others still sayiing there is no non-invasive tests available. We clearly have seen evidence that non-invasive testing, including antibody binding, TH1/TH2 ratio and Natural Killer (NK) assay can be useful guide in treating NAIT. Of the seven treated NAIT cases I am aware of that used these tests, the birth counts were 152k, 194k, 265k, 56k, 42k, 56k and 127k, and testing appeared to correlate to the results in six of the seven, and in the other case we were not provided the doctor's determination on the tests. The full text of this article is availble through the above link.
I found this research fascinating a few years back and that that a monoclonal antibody (H22) looked to inhibit antibody binding as effectively as IVIG in the testing. I contacted Professor Rodeck and he said while promising, there are still hurdles to clear. Here is the conclusion of the study:
"In conclusion, our results suggest that FccRI plays a major role in anti-HPA-1a-mediated platelet phagocytosis by mononuclear phagocytes while FccRIIa, is of little or minor importance only. Any role of FccRIII in the process has to be studied with macrophages as effectors. Moreover, the findings indicate the use of H22 as an alternative to ivIg in the management of the FAIT/NAIT."
Blockade of maternal anti-HPA-1a-mediated platelet clearance by an HPA-1a epitope-specific F(ab') in an in vivo mouse model of alloimmune thrombocytopenia. , Transfusion. 2009 Feb;49(2):265-70. Epub 2008 Nov 4.
A more recent article with a similar study to the one above using monoclonal antibody (MoAb), SZ21.
This article gives good basic information about NAIT (AIT) and what causes it, how to treat a newborn and information on Dr. Bussel's ongoing study. What I found most encouraging is they do not seem to be pushing the PUBS/FBS as much as they used to, and given their past published percentages of serious complications resulting from PUBS/FBS, it seems they are hopefully realizing what we and others saw in their data years ago and that is the rewards generally do not seem to outweigh the risks of the procedure. The article states: "In the past, we advocated fetal blood sampling to determine response to therapy. All current treatment programs minimize or even eliminate the use of fetal sampling."
This article covers a large study that concludes that 66% of the cases where a sibling had a servere count less than 20k, but no ICH, were already severely thrombocytopenic prior to treatment. I feel this is a strong argument against waiting until 20 weeks to treat. Here is an exerpt from the article we purchased:
"In conclusion, 92% of cases with a sibling history of antenatal ICH had severe thrombocytopenia prior to treatment at a median gestation of 24 weeks, and 66% of cases with a sibling platelet count of < 20 x 109/l also had severe thrombocytopenia prior to treatment at a median gestation of 28.5 weeks. The high incidence of hazards associated with FBS and the effectiveness of maternal therapy suggest that maternal therapy without an initial FBS should be used as initial therapy in these groups. This should be considered from or before 16-weeks gestation in the cases with antenatal ICH, because the earliest reports of ICH are at 16 weeks (Murphy et al, 1994), perhaps starting maternal therapy a few weeks later in the group with a sibling history of severe thrombocytopenia but no antenatal ICH."
We have heard of some moms via email that they had severely thrombocytopenic babies, were tested to have incompatible platelet type with the father, but had no anti-platelet antibodies detected. This article may help shed some light to the limitations of antibody testing. I know of a few others that I hope to post soon, or please email me for them if needed sooner.
The Bussel, Berkowitz, McFarland articles all provide a lot of useful data. While I do not agree with some of their conclusions (especially on what warrants early treatment), the data is useful and it helps highlight the serious complications they have encountered with the PUBS/FBS procedure in a significant percentage of their cases.
This study states that "In 48% of the ICH cases, the previous sibling had thrombocytopenia but not ICH." I feel this raises some questions to Dr. Bussel, Bekowitz, McFarland, etal's conclusion that an ICH is the only reliable predicter for what babies warrant early IVIG. Our question was why wait for something bad to happen before treating earlier? We were told by one doctor that in the unlikely event we did have an ICH if we started treatment later like he recommended, that he would treat us earlier on the next one. I can think of no parallel in medicine that uses this approach of requiring one of your children to possibly die of the same disease before treating a sibling more cautiously. This is just one more reason we felt Dr. Beer and Dr. Kwak-Kim were the doctors we wanted to use to manage our NAIT treatment.
Books:
Note: All articles are copyright of their respective owners
The Obstetric Hematology Manual by Sue Pavord and Beverley Hunt (Hardcover - May 24, 2010) This book contains a chapter (5) by Michael Murphy that basically states the protocol of J. Bussel, R. Rayment and Dr. Murphy.
Alloimmune Disorders of Pregnancy: Anaemia, Thrombocytopenia and Neutropenia in the Fetus and Newborn by Andrew Hadley and Peter Soothill (Paperback - Aug. 22, 2005)
We have correpsonded with Dr. Soothill and he is well versed in NAIT. While the information in this book is informative, it is not a super easy read for a lay person.
Platelets in Hematologic and Cardiovascular Disorders: A Clinical Handbook (Hardcover) 1 edition (January 14, 2008)
Basically another chapter by Dr. Bussel, but it does seem to offer a few more insights on some areas than his articles. He at least seems sensitive to intitial sensitization of a homozygous mother, but alas I am not sure he gives any consideration to increasing the sensitization in a previously sensitized mother. Others mention this risk when performing FBS/PUBS, but some in the US did not seem to write much on this until after the van den Akker, et. al., BJOG article seemingly changing direction of FBS once and for all.
NOTE and DISCLAIMER: My wife and I are not doctors. We are just parents who hope to share information we learned from reading and consulting with many wonderful doctors. The information, opinions, and reference materials contained in this site are intended solely for the informational purposes of the reader and should not be considered medical advice and is not intended to replace consultation with a qualified medical professional. This site is only intended to possibly help you when you are discussing NAIT with your own physician(s). |
This page was last modified on Monday, November 07, 2011 10:52:11 AM