IVIg for ART and Implantation Failure Controversy by Geoffrey Sher, M.D.

Body: 

The controversy regarding immunologic implantation failure and failed IVF has become a political football. The individuals who criticize the use of heparin/IVIG in IVF implantation are the same ones who originally criticized immunologic factors as causative in non-chromosomal "recurrent miscarriages". Now that the roll of immunology in the latter has been established and IVIG/heparin therapy has been accepted as a standard of care in the treatment of "unexplained" recurrent miscarriages, the same critics have turned their attention to the IVF arena.

There is an ongoing and deliberate agenda (on the part of a few) to discredit immunologic testing and the use of heparin/IVIG in IVF. In support of this position, the critics argue neither a positive relationship between APAs (antiphospholipid antibodies) and poor IVF outcome, nor a benefit from selective immunotherapy has been proven through randomized and controlled studies. In this they are correct. No one in our field would deny that the "gold standard" for scientific validation, is proof through the performance of randomized and controlled prospective studies. Yet, virtually nothing we offer patients in IVF has been validated in this way, ...not the protocols we use for ovarian stimulation, not IVF versus GIFT or ZIFT or IUI, not Clomiphene vs. Pergonal/Gonal F /Folistim, not Lupron vs. Antagon/Cetrotide, not Assisted Hatching, not ICSI, not one type of culture media over another, not day 3 vs. Day 5 (blastocyst ) embryo transfers, not progesterone vs. hCG vs. no support of the luteal phase...and the list goes on and on. In fact if the IVF literature were to comprise only those things that have been proven by this "gold standard", it would probably be less than one page in length. There are so many variables associated with IVF outcome:

 

  • woman's age,
  • number of prior failed IVF attempts,
  • protocols used,
  • timing for hCG injection,
  • method and duration of ovarian stimulation,
  • the collective and/or individual prowess of the M.Ds, embryologist(s),who perform embryo transfer( ET)
  • the catheter used,
  • loading technique,
  • time taken,
  • ultasound guided vs non-ultrasound guided,
  • uterine lining,
  • immunologic factors,
  • type of luteal support and

 

It is virtually impossible to evaluate the influence of a single variable on outcome, by this approach. At best one would be making an educated guess. This explains why almost all advances in the IVF arena have been as a result of controlled longitudinal cohort studies rather than randomized controlled studies.
There appears to be a double standard when it comes to immunologic implantation failure. I believe the double standard is attributable to the introduction of financial considerations. Consider the following:

 

By and large IVF is paid for on a fee for service basis and the IVF medical arena is highly competitive, with more than 360 IVF programs in the US competing annually for about 80,000 cycles of treatment. In most States IVF constitutes an out-of pocket expense to the consumer. Since immunotherapy is expensive (IVIG costs about $60 per gram and full treatment can require 40-80 grams), it is very difficult for the RE to persuade couples to agree to IVIG treatment, and at the same time remain competitive in the IVF arena. At the same time, competitors, slam this treatment as being exploitatory.

 

Central to the controversy regarding immunologic implantation failure and selective immunotherapy is the association between the presence of circulating antiphospholipid antibodies (APA) and activated Natural killer Cells (NKa). When it comes to the role of APAs, there is published data supporting both sides of the argument. The problem with regard to interpreting APA data is that there is no commercial Kit available that tests for all 21 APA's. So each laboratory has to develop its own reagent process. There is also currently no uniform agreement on the exact cut-off values to use in deciding on a "+ve vs. a -ve" result. The truth is that most RE's still rely on non-specific and relatively insensitive tests such as PTT, lupus anticoagulant and anticardiolipin antibodies. Relatively MD's in the IVF arena measure an entire panel of 18-21 different types of APAs and as stated above, most immunology laboratories vary in the methodology they use and disagree on the exact cut-off points beyond which reported results should be regarded as "positive" or "negative".

 

The origin of most of the contrary information regarding APA testing stems primarily from an article by Denis and Scott, et.al. which appeared in "Fertility and Sterility" in 1997. This article reported on an absence of any correlation between APA+ and IVF outcome and was, in my opinion, seriously flawed in design and methodology, sufficient to evoke a flurry of strong criticism by way of letters to the editor in a subsequent edition of the journal . The critics cited the following significant problems with this study :

  • First, the IVF patients reported on were not confined to those with female causes of infertility. (We have never claimed that APA positivity has any significance in cases where IVF is done for an isolated male factor). In fact about one half of the cases reported by Denis and Scott had male infertility as the primary indication for IVF
  • Secondly, the methodology for APA testing in this study was shown to be seriously flawed and lacking both in sensitivity and specificity. About a year ago we reported in "Human Reproduction" on a positive association between the presence of certain types of APAs and increased NKa in the blood.

 

More recently we have shown that when IVIG is given to APA+/NKa+ women (>200 cases) the pregnancy rate is comparable to negative testing IVF patients . AND subsequently out of 21 women NKa+ women who refused IVIG/heparin, only one(1). conceived. After reconsidering the situation, 8 of those who did not take IVIG and failed to conceive, came back and did IVF again, this time using IVIG/heparin. About half of these women conceived straight away. We believe that the evidence shows that many APA+ women who undergo IVF for female factors, will not achieve viable pregnancies that continue to delivery without minidose heparin therapy and if in addition, they test NKa+ less than 10% will have IVF babies unless IVIG is added to the heparin regime.

Against this background we recently initiated a long awaited randomized and controlled study that will, hopefully, settle this controversy. This IRB approved study addresses, the use of IVIG/heparin therapy in APA+/NKa+ women undergoing IVF and confirm what our prospective longitudinal cohort studies have already shown , namely, that selective immunotherapy significantly enhances IVF outcome. In an attempt to reduce the number of confounding variables, we intend making the qualifying criteria tight, performing all IVF at a single SIRM center , and confining the performance of IVF to the same two(2) treating physicians and the same embryologists, throughout.We anticipate that it will take about eighteen (18)months to complete this study. Enrolment has already started.

 

If you are interested in participating and would like to determine whether you qualify, please contact Linda Danner R.N at "ldanner@sherinstitute.com" or call 800-780-7437 ASAP . SIRM is accepting enrollees on a first come first serve basis.

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