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Fruit of the Womb
Fruit of the Womb

Plasminogen Activator Inhibitor 1 (PAI 1) and Recurrent Pregnancy Loss

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Back in June, a reader I.R. left a comment on my post "Recurrent Early Pregnancy Loss - 7 - Immunologic a...". Her specific question related to the possible role of plasminogen activator inhibitor 1 (PAI 1) activity and polymorphisms in recurrent pregnancy loss. The question interested me so much at the time, that rather than answering it in cursory fashion, I promised her I would review the current literature and devote a full post to the issue “in the near future.” Despite my having been, repeatedly, sidetracked, I.R. has remained a loyal reader, and insightful patient, and updated me regularly on her progress. Today, in the paragraphs below, I am going to summarize (and modify for clarity) her story with excerpts from her comments and then summarize my thoughts on the issues she has raised in a follow-up post ….

Dr. Trofatter, I have been diagnosed with Recurrent Pregnancy Loss. I've lost three early pregnancies- 6 weeks, 7 weeks, and 4 1/2 weeks- over the last year. After the third loss, my husband and I went through testing in March 2007 and it's been determined that I have a PAI 1 (4G4G) genetic mutation… I am a healthy 26 year old. I have found a wonderful hematologist that goes above and beyond for me. However, I'd like to know your perspective of how PAI 1 correlates with early first trimester miscarriages… I am having a difficult time finding much information on PAI 1 and miscarriages. It seems that most blood clotting disorders cause second trimester miscarriages; however, I feel that scientists and doctors are still building correlations between clotting and early first trimester losses. Thanks for any advice! I.R.

In August, this was followed by another comment on my post "Diabetes in Pregnancy - 2 - Glucose Metabolism and...":

Dr. Trofatter, I have yet another question. My last miscarriage was in February. I have been trying to get pregnant all summer…using ovulation sticks. Does PAI 1 have anything to do with me not being able to conceive? I've mentioned to two of my doctors the connection of PCOS (polycystic ovary syndrome) and PAI 1 and they all agree that I do not fit any of the typical picture of PCOS; however, after asking for a glucose/insulin test, I am now scheduled to get one. Do you think this is a good step? I know that PAI 1 has something to do with insulin which has to do with the endocrine system which can affect ovulation. I've never had issues in the past getting pregnant, just maintaining my pregnancies. I do not have diabetes. Any advice would be greatly appreciated! No matter how much I try to research PAI 1 and recurrent pregnancy loss, I can’t seem to understand it. Thanks so much for your time! I.R.

A few weeks later, I.R. left another comment on the same post…"Diabetes in Pregnancy - 2 - Glucose Metabolism and..." (sometime I have really got to finish up that series too!)…

Hi Dr. Trofatter, Low and behold, after a few months of asking for an insulin/glucose test, my wish was granted last week. I received my results yesterday and both fasting tests were normal and my two hour glucose was normal as well; however, my two hour insulin levels were elevated which is evidence of insulin resistance…I have mentioned the correlation of PAI 1 and insulin to my doctors a couple of times before but was essentially dismissed because I don't fit the "criteria" of a person who has insulin resistance. I'm not overweight at all and I'm not inactive…I start glucophage with hopes of increasing the quality of my ovulation. I do ovulate "regularly" on CD 15. What are your thoughts of taking glucophage (Metformin) while pregnant?...I know that it is controversial either way. I would appreciate any insight about the connection of PAI 1 and early trimester pregnancy loss as well as its connection to insulin.
Hope you're doing well! IR


I actually did respond briefly to this query and my comment included the following thoughts: There indeed appears to be a need to increase insulin sensitivity in first trimester to aid in proper implantation and placentation...I bet you will be home free from the baby's standpoint if you can get past twelve weeks...You will still be at increased risk for gestational diabetes...While you're at it, why don't you throw the progesterone support, baby aspirin, extra folic acid, and heparin or Lovenox into the mix as well...The latter I would not begin until a pregnancy is confirmed chemically (just about the time you miss a period)... Hang in there girl. I wish you the best on this and think you are going to be a great MOM! Dr T

Then, within two weeks of the above, the following comment was received from I.R.…

Hi Dr. Trofatter, I am on calendar day (CD) 31 and had a positive pregnancy test on CD 27. :) I started Lovenox and am continuing low dose aspirin, my prenatal vitamin and because of the insulin resistance diagnosis, I began glucophage on CD 23. I talked with my nurse today about a calcium supplement and also mentioned the glucophage. She talked with my doctor and she said that he wants me to stop taking glucophage. According to him, since I never made it to the maintenance dose (the 3 pills each day), then it isn't doing anything to help me. I've read elsewhere though that it can help prevent MC. She said that they only wanted me on it to regulate my ovulatory pattern, which does make sense to me, even though I do ovulate regularly just at a later day than 14. My question/concern is that my doctor isn't giving any thought to his decision of stopping glucophage and my diagnosis with PAI 1. This is such a big deal to me…I want to call again tomorrow, but would like a second opinion about my feelings as to whether they're rational or not! I really do like my RE (reproductive endocrinologist) and know that he's performed miracles for many women… Thoughts??!! Thanks again for your insight and time! It means so much! I.R.

To summarize I.R.’s many questions and to throw in a few of my own…
1) What is PAI 1 and what are its roles?
2) What is the association between PAI 1 activity and recurrent pregnancy loss?
3) Should screening for PAI 1 be a part of our regular evaluation of the couple with recurrent pregnancy loss?
4) What is the association between PAI 1 activity and insulin resistance?
5) Could PAI 1 activity be associated with infertility?
6) What role might glucophage play in the management of women with recurrent pregnancy loss and abnormalities of PAI 1 activity?
7) If glucophage is used in women with ‘insulin resistance’, is there a benefit to continuing it during pregnancy or should it be stopped, and when?
8) In the absence of clinical indication other than recurrent pregnancy loss, should the other medications (Lovenox and aspirin) be continued or stopped and when?

Actually, if I had all the answers to the above questions (and I am sure I will come up with a few more as I try to answer these), I would probably be quite famous, but in our next post on this subject, I will at least give you my thoughts! And, to I.R., thanks for your loyalty and your patience and best of luck with this pregnancy!
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