I am getting referrals regarding ladies with recurrent miscarriages getting workups from fertility labs for immunity. I am familiar with elevated NK cells accounting for miscarriages, but not knowledgeable about test for "leukocyte antibody detection" as well as TSH levels less than 1.5 and serotonin greater than 100 showing increased risk. The patient also showed testing for plasminogen activator inhibitor as having a heterozygous expression of 4G.

Is there a good source for science regarding reproductive immunology to help interpret the validity of these tests from these labs?


Thank you for your inquiry.

I am not personally aware of any source that would help you with this problem, but I am referring your inquiry to Dr. Robin Fogle with the Atlanta Center for Reproductive Medicine. As soon as we receive his response, we will forward it to you.

Thank you again for your inquiry.

Phil Lieberman, M.D.

We received a response to your Ask the Expert inquiry from Dr. Robin Fogle with the Atlanta Center for Reproductive Medicine. Thank you again for your inquiry and we hope this response is helpful to you.

Phil Lieberman, M.D.

Response from Dr. Robin Fogle:
Thank you for reaching out to me with your colleagues' questions regarding fertility testing. I apologize for the lengthy delay in responding. Please see my responses below.

There are multiple potential causes of recurrent pregnancy loss (RPL), many of which are well documented and accepted in the mainstream reproductive endocrinology community. Alloimmune factors, however, are not among those causes as they have not been proven in a rigorous scientific manner to play a role in RPL. In fact, the American Society of Reproductive Medicine (ASRM) has clearly stated in their committee opinion on RPL, that alloimmune factors not be investigated as a source for RPL in patients. The current list of topics falling under the category of "controversial" scientific evidence in support of role in RPL" includes: Mucosal CD16 NK cells, embryotoxic factor, cytokine profiles, blocking antibodies, HLA typing, anti-paternal leukocyte antibodies, and circulating CD 16 NK cells. The committee has been so direct as to state that circulating CD 16 K cell testing not be undertaken in these patients. Below is an excerpt from that committee opinion regarding alloimmune factors.

"Studies of human leukocyte antigen (HLA) typing, embryotoxic factors, decidual cytokine profiles, blocking or antipaternal antibody levels, HLA-G polymorphism, and other immunologic traits and factors have produced inconsistent data that generally have not been reproduced in more than one laboratory. Proposed immunomodulatory treatments for RPL in the setting of one or more of these findings have not been proven effective.

A meta-analysis of trials on paternal white blood cell immunization concluded that it had no beneficial effect (83). Treatment with intravenous immunoglobulin (IVIG) has also been proposed for unexplained pregnancy loss. However, several trials and meta-analyses concluded that IVIG is ineffective for primary recurrent pregnancy loss (84-88); thus, this treatment is not recommended." Fertil Steril 2012; 98:1103-11.

With regards to the questions regarding a negative impact of TSH levels less than 1.5 mIU/L on pregnancy, I am unaware of any literature in our field supporting this. We have made a concerted effort to keep TSH levels between 0.5 and 2.5 mIU/L in our patients who are attempting conception. Again, I have included an excerpt from the American Society for Reproductive Medicine committee opinion on RPL evaluation as it related to thyroid testing.

"As long as thyroid-stimulating hormone (TSH) levels are in the normal range, there is insufficient evidence to recommend routine thyroxine (T4) testing or screening for anti-thyroid antibodies (60). However, this is problematic given the lack of consensus regarding the definition of a normal upper limit of TSH. Whereas TSH values of 4.0-5.0 mIU/L were once considered normal, a consensus is emerging that TSH values above 2.5 mIU/L are outside the normal range."

I am unaware of any literature suggesting an increased risk of miscarriage with serotonin levels greater than 100, although evidence does suggest an increased risk of miscarriage in patients using SSRIs in early pregnancy.  

Lastly, there is no convincing data at this time to suggest an increased risk of miscarriage in patients with the heterozygous 4G/5G PAI-1 genotype. A retrospective study by Dossenbach-Glaninger et al, 2003, showed an increased risk of the PAI-1 SERPINE1 4G/5G genotype in patients with RPL. However, a subsequent metaanalysis of 5 studies, which included the above study, did not show a difference in the prevalence of the homozygous mutant 4G/4G genotype between controls and RPL patients. Two of the studies were analyzed and the integrated data showed that high PAI activity levels are not associated with recurrent miscarriage. Obstet Gynecol 2007; 109:1146-55.

I hope the above information helps. The evaluation of RPL is certainly one of the most difficult challenges we face as reproductive endocrinologists. The etiologies are vast and, in many cases, unknown.  The data on reproductive immunology is accumulating rapidly and will hopefully add some additional insight into RPL and its treatment in the near future.

With Regards,
Robin Fogle, M.D.

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