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Very few topics generate as much controversy amongst fertility specialists as the impact of abnormal autoimmunity on female fertility. In our opinion (for a detailed list of articles, published by CHR’s Medical Director, Norbert Gleicher, MD, on this topic, or to outline your autoimmune infertility issue please contact us), abnormal autoimmune function represents a quintessential reason for female infertility and can take the form of various clinical presentations. Indeed, we believe that, overall, abnormal autoimmunity may represent the most frequently overlooked, and underappreciated, cause of female infertility.
Does abnormal autoimmune function cause infertility?
Most fertility specialists agree that, at least indirectly, abnormal autoimmune function can cause infertility by inducing repeated pregnancy loss. When asked whether abnormal autoimmunity can cause infertility directly, most will, however, deny such an association.
This is actually very surprising because there is, by now, quite convincing evidence in the medical literature that women with many autoimmune diseases, indeed, suffer from decreased fertility (the correct medical term is fecundity; i.e., the ability to spontaneously conceive). Amongst the autoimmune diseases in which decreased fecundity has been demonstrated are systemic lupus erythematousus (SLE), rheumatoid arthritis, scleroderma, autoimmune thyroid disease, multiple sclerosis and others. What is, however, even more suggestive of a potential autoimmune etiology for some female infertility is the fact that in all of these conditions the decreased fecundity already exists for years before the autoimmune disease is clinically apparent and diagnosed.
This is a very important observation because it suggests that abnormal autoimmune function, even in so-called preclinical stages, already can negatively affect the ability of women to conceive. Preclinical stages of autoimmune diseases precede practically any active autoimmune disease and they are characterized by the presence of autoimmune abnormalities in blood, in the absence of clinical signs and symptoms. Such abnormalities are, therefore, frequently called sub-clinical in nature. Sub-clinical autoimmune abnormalities do not only occur in women who are destined to develop autoimmune diseases. They also occur frequently in women who will never develop a specific autoimmune disease. Good examples are relatives of individuals with autoimmune diseases. First degree relatives of individuals with autoimmune diseases have been reported to have as high as a 40 percent chance of having autoimmune abnormalities in their blood, most of the time with complete absence of any symptoms of disease.
How to make the diagnosis
This observation is, at least in part, a reflection of the fact that the predisposition to autoimmune diseases is highly familial. This means that, if you have a close family member with an autoimmune disease, you are at increased risk for autoimmune diseases. As is now widely believed, this familial predisposition towards autoimmune diseases is not restricted to one specific disease, but to autoimmune diseases in general. In other words, if your mother has SLE, you are not only at increased risk for SLE, but for all autoimmune diseases. Dr. Gleicher demonstrated this fact, once again, in a study which was last year published in the Journal of Autoimmunity (Gleicher et al., J. Autoimmunity 2006; 27:161-5). Sub-clinical autoimmune disease, only detectable by appropriate blood testing, is, therefore, a quite frequent phenomenon and will be diagnosed only if treating physicians, based on detailed family histories, are suspicious enough to order the appropriate testing.
Autoimmune diseases, even if symptomatic, are also often difficult to diagnose because the symptomatology can be very non-specific. Indeed, women (and men) can go for years without a specific diagnosis, even though they may experience quite typical (though non-specific) symptoms, such as arthritis, tiredness or atypical skin rashes. Making the correct diagnosis can be further delayed by the fact that autoimmune diseases quite typically go through periods of exacerbation (flares), often followed by prolonged periods of remission of symptoms. Disease activity is, thus, uneven and, therefore, at least in the early stages of the disease, often dismissed.
Sub-clinical disease can, of course, also go through periods of flares and remissions and, therefore, laboratory abnormalities will not always be present. Physicians often erroneously dismiss a possible autoimmune diagnosis when laboratory abnormalities are absent, failing to recognize that they may have simply tested during remission. This inconsistency of laboratory testing in women with sub-clinical autoimmune diseases has been one reason why many authorities in the infertility field have been dismissive of autoimmune testing. They, unfortunately, do not understand the natural history of abnormal autoimmune function.
Autoimmunity and pregnancy
Pregnancy has a major effect on abnormal autoimmune function. It is well established that pregnancy can affect autoimmune diseases. How this happens and why differences are observed between different autoimmune diseases is not well understood, yet. A few principles deserve, however, further discussion: One general principle is that many, if not most, autoimmune diseases have a tendency to exacerbate with pregnancy. Two periods of pregnancy are of particular interest: the very early stages of pregnancy and the very end of pregnancy, reaching up to approximately three months into the postpartum period.
In early pregnancy, autoimmune flares are characterized by pregnancy loss. In late pregnancy, and the postpartum period, one usually observes outright disease flares. There are complex immunological explanations for the timing of these flares, which relate to the fact that pregnancy, from an immunologic point, represents as situation akin to an organ transplant since half of the fetus is genetically the father’s. The maternal immune system, therefore, has to “tolerate” this transplant. There is considerable evidence in the literature that these autoimmune exacerbation periods reflect abnormalities in the normal immunologic tolerance of the fetus. (For more detail, please see Dr. Gleicher’s lead article in the January 2007 issue of the American Journal of Obstetrics and Gynecology.) Pregnancy can, therefore, induce autoimmune reactions in women who, otherwise, may never have shown autoimmune abnormalities, and baring further pregnancies, may never again do so.
Conclusions
The latter conclusion can not be overemphasized in its importance because it means that autoimmune abnormalities may never be detectable, unless a patient is pregnant. This is one explanation, why approximately 20 to 25 percent of women with repeated immunologic pregnancy loss will not show autoimmune abnormalities in their blood, unless they are tested when pregnant. Another, and maybe more determined way of saying the same thing is that, even in the absence of confirmatory laboratory tests, an immune etiology for repeat pregnancy loss should be suspected if clinical presentation and history raise such a possibility. Only if laboratory tests are negative, once a positive pregnancy test has been obtained, can an immune problem be ruled out for this pregnancy.
The emphasis is on this pregnancy because, though unlikely, the patient may in a subsequent pregnancy react differently. Two possible explanations for different immunologic behavior in subsequent pregnancies are possible: A different paternity may elicit an immune response, where the current paternity has not. (It has been demonstrated in conjunction with rheumatoid arthritis and scleroderma that the likelihood of an autoimmune flare is increased if father and mother are genetically similar, and is diminished if their genetic make up is more divergent.) Or, alternatively, the woman may be at different stages of her flare-remission pattern.
For further information on Autoimmunity and Infertility, please visit our Autoimmunity Website .
IVF Pregnancy Rates at CHR Doubled in 2006 in Women above Age 40
It is well known that IVF pregnancy rates decrease with female age. This decrease accelerates after age 40 and pregnancy rates are, therefore, progressively poorer as women age beyond 40 years. As readers of our UPDATEs know, we have been treating selected women at those ages with DHEA. The year 2006 was, indeed, the first year in which this has been happening systematically. All qualified patients above age 40 received at least two months of DHEA supplementation before going into an IVF cycle.
We, therefore, had been looking forward to the end of 2006 to analyze whether this change in our treatment approach for older women had affected our annual outcome statistics after IVF. This analysis is now complete; however, before presenting the quite exciting data, we need to clarify some important issues:
(i)We do not treat every woman above age 40 with DHEA. Indeed, in order to qualify for such supplementation, patients had to have failed at least one prior IVF cycle and had to show poor embryo numbers, poor embryo quality, or both.
(ii)A large proportion of patients, treated with DHEA at our Center (over 60% of the patient pool) came to CHR after having been told at other centers that their only remaining option was oocyte donation.
(iii)Patients treated with DHEA represented, what in medicine are called an “adversely selected” population; i.e., women with below average chance of pregnancy.
(iv)They are, however, because of their low outcome chances, an ideal study group to demonstrate statistically significant treatment benefits.
CHR-NY, Clinical Pregnancy Rate/Per Transfer
(January, 2006 to December,
2006)
The table above shows CHR’s 2006 IVF outcome data. Please note that clinical pregnancy rates are listed as percentages in reference to embryo transfers. Delivery rates for 2006 are not known yet. Miscarriage rates between 2003 and 2005 were, however, surprisingly low. Consequently, at least for those years, there was no statistical difference between ongoing clinical pregnancy rates and delivery rates in this patient population.
These 2006 numbers are, of course, not only remarkable because they demonstrate a statistically significant improvement over the years 2003-2005; they are especially remarkable because of the patients involved. CHR does not limit access to IVF, based on mild to moderately abnormal baseline FSH levels. Indeed, we accept patients into IVF up to baseline FSH levels of 40mIU/ml. CHR also does not cancel IVF cycles before retrievals, if minimum follicle numbers are not reached. We feel that cycle cancellations in such patients do not make sense, since future cycles will, most likely, not improve follicle numbers. Consequently, we will go to retrieval with even one or two follicles. As a consequence, our cycle cancellation rate for this group of patients has consistently been very low, in a range of 10-15%.
The outcome data presented in the table, therefore, represent a completely unselected, and unfavorable group of patients with amazingly excellent outcomes. They represent a respectable sample of 281 cycles. These data are, however, further enhanced by the fact that, almost a similar percentage of patients on DHEA, as we have reported before, conceive spontaneously while on DHEA, and waiting for an IVF cycle. As a consequence, approximately a third of patients, who have come to CHR after referrals into egg donation, leave CHR with an ongoing pregnancy.
In the title to this segment we note that this observed improvement in IVF outcomes is probably due to DHEA.
While we are very convinced that consistent DHEA supplementation in qualified patients has given us these results, there is, of course, always the possibility that other program changes may also have contributed. Since we have not introduced any protocol changes in 2006, and since our clinical and embryology staff has remained the same, such an explanation is unlikely. Moreover, our 2006 patient population has become more unfavorable (as previously defined) in comparison to earlier years. One, therefore, would actually expect a lowering of pregnancy rates. Because confounding factors can never completely be ruled out, we, as always, want to be cautious in our attribution of causation and, therefore, the word “probable.”
If you are interested in further information on Premature Aging Ovaries and DHEA, please visit our Aging Ovaries Website.
No Placebo Here!
Probably the most exciting news in our continuous efforts to investigate the beneficial effects of DHEA supplementation on the ovary, is that the prospectively, double blinded, randomized study, which we started at the beginning of the year in collaboration with a number of European centers, is progressing well. Our European colleagues are, indeed, succeeding in enrolling patients into this placebo-controlled trial and we expect, at least preliminary results, by year’s end.
Since this study was formally registered as a clinical trial, we received innumerable requests from U.S.-based women to participate. Unfortunately, this study is, for cost reasons, only conducted in Europe. Patients, who wish to be considered for DHEA treatment in the U.S., have to become one of our patients. The potential advantage here, of course, is that you don’t run a 50% risk of being treated with placebo.
We are pleased to report that the Foundation
Research the
Foundation for
Reproductive Medicine (FRM)
was formally awarded not-for-profit status by the IRS. This means that contributions to the FRM wll now be fully tax-deductible in accordance with the law. Since FRM has for many years been financially supporting much of the research at CHR, we strongly encourage donations to FRM.
If you are interested in
contributing to our
Foundation, either financially
or through organizational
efforts, please visit our FRM Website.
We greatly appreciate all
help!
Dr. Gleicher and CHR helped my husband and I conceive twins with PGD about 3 1/2 years ago (working with Dr. Mark Hughes) I just wanted to send a note and tell you how grateful we are for the work you and the rest of the clinic and lab are doing. Allison and Rachel are very happy, healthy, bright, beautiful two-year olds and we could not imagine our lives without them.
Earlier this year my husband was diagnosed with Huntington's Disease. While his diagnosis is a very difficult thing for our family, I can not put into words how grateful I am that I do not have to worry about my daughters having this devastating disease. I also know that as my husband faces his own illness he does not have to suffer with the guilt of passing it onto his children. And what a blessing for them to not have to grow up in fear.
I sat in a support group meeting on Monday and listened to a woman say that she just started to notice symptoms in her nine-year old son. It made me think how very lucky I am and how grateful I am for your work.
Please share this note with anyone at the clinic you think appropriate.
Sincerely, Kelly Haab St. Charles, IL
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Dear Dr. Gleicher, Dr. Barad and staff,
My husband and I came to you in January of 2003 for a consultation. After one unsuccessful attempt, you advised me to go for surgery. After the surgery, we started another IVF cycle. On August 28th, I became pregnant with my beautiful little boy who was born on May 13, 2004 . He is now 7 1/2 months old and we just celebrated our first Christmas together as a family.We are so happy that we are considering to add to our family, with your help, of course.
Thank you for being professional, caring and wonderful people. From our family to you all, have a happy and healthy New Year. L. Mancini
Would you like your CHR experience featured in a future edition of The Voice? An ongoing open call has been established for all CHR patients interested in sharing their experience, or simply featuring pictures of their bundles of joy. If you are interested in submitting your experience or pictures, please e-mail us.
Editor:
Tom Weidner - tweidner@thechr.com
Developmental Editor: Alexia Scarpinato - ascarpinato@thechr.com
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