Plasminogen Activator Inhibitor 1 (PAI 1) and Recurrent Pregnancy Loss
Sunday, September 30, 2007
Kenneth F. Trofatter, Jr., MD, PhD
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!
Labels: diabetes; insulin resistance, glucophage, lovenox, PAI 1, PCOS, plasminogen activator inhibitor 1, recurrent pregnancy loss, thrombophilias
24 Comments:
At Mon Oct 01, 05:58:00 AM 2007,
Anonymous said…
Dr. Trofatter,
I'm actually having another miscarriage. :( I did stop the glucophage as was recommended by my doctor. He mentioned that since my glucose levels were normal, then he didn't see a point and was honestly unsure as to whether or not the glucophage would benefit me or not. So, I, reluctantly, stopped. Four days later, my numbers stopped doubling and now the miscarriage is impending. Who knows if there is a correlation there or not, maybe or maybe not. The "what ifs" are always difficult. I am trying to remain hopeful (which is difficult after four miscarriages)...thinking that perhaps the egg quality wasn't the best to begin with because I wasn't on glucophage/metformin through ovulation. I usually get the LH surge on CD 15, which leads to a "later" ovulation time. I did have my follicle and lining looked at upon ovulation and everything looked good. When I feel up to trying again in the future, I plan to stay on the glucophage before and during early pregnancy- maybe it's the one ingredient that I missed. Again, thank you for your follow ups. Your advice and expertise is more than appreciated. I am looking forward to reading your thoughts! Izzi
At Mon Oct 01, 08:50:00 AM 2007,
Anonymous said…
Sorry, that should have been 6 weeks, not 6 months! (revision below)
So glad to see this post! I am also 4G/4G homozygous for PAI-I and also homozygous for MTHFR (both C and A mutations) and had 4 early first trimester losses (all around 6 weeks). In my last pregnancy, I was on 30 mg Lovenox twice a day, 81 mg aspirin, progesterone, prenatal vitamins, and large "extra" doses of folic acid, B12 and B6. I am happy to report an uncomplicated, successful pregnancy, resulting in a beautiful baby girl! I sympathize with your reader and wish her success in this pregnancy. One doctor had suggested metformin for me but the other doctors on my team overruled this prescription claiming that I had no risk factors for PCOS or other insulin resistance. And so now a question, Dr. Trofatter, I would like to conceive again but am still nursing my almost 2 year old. My doctors have suggested taking the 81 mg aspirin out of the mix for this next attempt as they suspect aspirin does not have much impact on my condition and Lovenox is safer for nursing. Any thoughts on this? Thank you for writing this blog! I cannot tell you how great it is to see a doctor focusing on blood clotting factors and pregnancy.
At Mon Oct 01, 10:33:00 AM 2007,
Anonymous said…
Dear Dr. Trofatter,
I am 30 years old and am currently going through my third miscarriage with my current husband. We have yet to have a child together, but we both have health children from our previous marriages. My husband has made an appointment to see a doctor to get his sperm analyzed. And I have a follow up appointment with my OB next week, for the D and C she performed last Tuesday. I guess my question to you would be what is our next step? My OB said that we can try again in two months but I wonder what can be done to prevent this from happening again. Going through a miscarriage isnt very fun, in fact its very painful. I never thought having a baby would be so hard. We dont have a problem getting pregnant but we have a problem staying that way. I am also looking into alternative medicine as well to see what they can do about my situation. What do you think?
At Wed Oct 03, 05:24:00 PM 2007,
Kenneth F. Trofatter, Jr., MD, PhD said…
To Anonymous Oct 1: Low-dose aspirin (81mg) is very effective at blocking the platelet side of the clotting system (Lovenox works on the other side of the clotting cascade). Although there is really not much literature on low-dose aspirin in lactating women, at least one review article has stated that doses less than 100mg/day appear to be very safe (Bar-Oz, et al., Drug Saf. 2003;26:925-35). Thank you for sharing your success story and best wishes in the future. Dr T
At Wed Oct 03, 05:29:00 PM 2007,
Kenneth F. Trofatter, Jr., MD, PhD said…
To Anonymous Oct 1 10:33 AM: What you do next depends on whether you want mor information or you just want to try again with empiric therapy. I have written a whole series onRecurrent Early Pregnancy Loss in March-April 2007. My last several posts on the subject summarize diagnostic and therapeutic approaches, including 'empiric therapy.' Why don't you read those posts and get back to me if you have any more questions. I wish you luck and thank you for reading! Dr T
At Wed Oct 03, 05:38:00 PM 2007,
Kenneth F. Trofatter, Jr., MD, PhD said…
To Izzi Oct 1: Girl, you tear my heart out. My suggestion is go all out next time if your doctors agree: ovulation induction, progesterone support, folic acid, baby aspirin, metformin, and therapeutic levels of Lovenox. I rarely use prednisone anymore, but you might even be a candidate for that. Stay in touch. I will be thinking about you. Dr T
At Fri Oct 05, 07:09:00 AM 2007,
Anonymous said…
Hi Dr. Trofatter, Thank you for your advice and concern. When thinking about the PAI 1 article you're going to write, will you also address the question: Should I begin Lovenox 72 hours after ovulation or with a positive pregnancy test? I believe that there could be benefit to starting at ovulation rather than waiting for a positive because the fertilized egg immediately finds a home in my uterus, "cutting" it and already beginning the clotting issue, which because of PAI 1, I am not dissolving. Your thoughts? In your comment, what do you mean by "therapeutic levels of Lovenox"?
I apologize for writing in so much, but I truly am fascinated by your comments and enjoy being educated by a doctor in the field. Off topic (kind of), do you consider insulin resistance to be the same as PCOS?
I genuinely appreciate your time. Izzi
At Mon Oct 15, 02:21:00 PM 2007,
Sarah said…
Dr. Trotter, I like the other woman, had recurrent pregnancy loss before twelve weeks. I had two miscarriages within a six month period. I went to a fertility specialist who diagnosed me with elevated PAI-1.
I never had any infertility problems, in fact, I got pregnant all three times (I am 6 months pregnant now) within one week of trying during ovulation.
As soon as I was pregnant, my doctor immediately put me on progesterone and lovenox and I am now a healthy six months pregnant with a baby girl. I do not have any insulin problems however I have suffered from high blood pressure since I was 19. I am now 30. I take 400 mg. of Labetelol daily to keep my hbp under control as well as the lovenox. I do not take baby aspirin with it.
I am hoping my story helps the other woman.
At Fri Oct 19, 07:52:00 PM 2007,
Kenneth F. Trofatter, Jr., MD, PhD said…
To Sarah Oct 15: Thank you for sharing your story. I know there are many women who will appreciate the hope you have given them by your confidence in, and response to, that therapeutic regimen! Dr T
At Wed Oct 24, 11:08:00 AM 2007,
Anonymous said…
Oh my goodness…today I went for an appointment with a new doctor to get confirmation about my treatment and any other recommendations. I just wanted to feel better about the path I was headed because my regular RE is more or less just guessing about my treatment, which I do understand that sometimes it is a thought out guess. The appointment went disastrously wrong…I cried an ugly cry during the appointment as the doctor went on his soap box about how all patients that are referred by an RE are on progesterone, Lovenox and Metformin. That they only ever use those drugs as empirical drugs. That there is no proof that any actually help carry a pregnancy to term. In fact, I was told that I have a 5o:50 chance,” you know, like flipping a coin,” the counselor said. And, according to the doctor, it’s a 50% chance of having a successful pregnancy without even trying any type of medicine whatsoever. I was told before my fourth loss by my hematologist that PAI 1 levels become elevated very early on in a pregnancy and that is why they can cause early miscarriages (she had more of an explanation that I don’t recall because I find it difficult to understand). Today, I was told by new doctor that 1:4 people have PAI 1 4G4G and that millions of them go on to have successful pregnancies so there’s no reason that it’s causing me to have my miscarriages. He believes that it’s just a “fluke” and that perhaps my random mutant genes are causing them. Which to my understanding is that in “one time” or “random” miscarriages, that is more than likely the case, but in recurrent losses, the chances are much less of it being an abnormality due to genes/chromosomes. I told him what my hematologist said and his rude response was that “she knows more about it than we do then.” I just don’t know what to do. Like I said, I’m not looking for miracles from a doctor (Yes, I’d love a miracle from God!) and I’m not looking for a guarantee, I am simply looking for hope from a doctor. Hope meaning that they’re going to be confident in our treatment so I can have more confidence and that they’re going to be proactive for my individual treatment plan. So, now, I guess I should try again with no medicine or treatment. I am being sarcastic with that statement…I mean why would I come this far and not try the treatments that have been recommended to me? I truly don’t understand how I can find research about diagnoses similar to mine and treatments like mine that lead to successful pregnancies, yet some doctors don’t give any credit the medication for the results.
I’ve told my RE in the past and went in to this doctor today and said that I don’t want to be naïve. Right now, I’m really hoping that the Metformin was my missing ingredient since I was diagnosed as insulin resistance. I’m hoping that my egg quality will improve and the next time I try with my treatment, it will be more successful. Yet, the naïve part comes to play in the fact that I do want to believe that whole-heartedly that Metformin will do the trick for me, yet how many women do not take care of their bodies, aren’t knowingly or unknowingly healthy and go on to have perfectly healthy, uneventful pregnancies. Why do all my “ducks have to be in a row,” a perfect row in order to have a healthy pregnancy?
So, perhaps I don’t need prometrium or even a daily dose of aspirin, but I really thought that my doctors prescribed Lovenox and Metformin because they believed that it is what I needed to have a healthy pregnancy and not another miscarriage. Are they in fact just being empirical in their thinking? I do find that hard to believe because there have been to many successes/miracles as a result of this treatment or treatments similar.
Sorry for the book and thanks for your time, Izzi
At Fri Oct 26, 04:58:00 PM 2007,
Kenneth F. Trofatter, Jr., MD, PhD said…
To Izzi: Just as there are bad studies to support the use of these drugs in recurrent pregnancy loss, there are equally bad studies that say they may not work. Notice I did NOT say there are lots of GOOD studies out there. Much of what we offer patients like you is in one sense of the word, 'empiric', simply because we aren't smart enough at this point to know EXACTLY what it is we are treating and why it seems to work in some and not in others. There are clearly circumstances where it is not just a 'flip of the coin.' The important thing in your case is that I do not believe ANY of the therapeutic regimens proposed to you are going to HURT you or a baby in anyway. You have to believe that and the doctor you saw, if you are portraying the interaction accurately, made a cardinal mistake in dealing with what is for you an extremely sensitive and emotionally charged issue - he undermined your hope. Don't let him do that. You have NOT exhausted all of your options, so even if things have been hard, try to hang in there...Wish I could be there to hold your hand!Dr T
At Sun Oct 28, 06:19:00 PM 2007,
Anonymous said…
Dr. Trofatter,
Thank you for your understanding response. While I am not at all one to embellish, I am the first to admit that I am an over-sensitive person and my feelings do get hurt easily. To be honest, your response brought tears to my eyes! So, thank you for your kindness. And, as you said, this is an “emotionally charged issue,” I was (am) extremely sensitive and his matter-of-factness really did hurt my feelings…it took me off guard. I was there to ask questions and to learn more and he didn’t stop talking about his beliefs, which educated opinions or facts, I did not want to hear because of the austerity in the way he presented them. You’re right, bottom line, he is not going to be my future doctor and I can’t let him (or anyone) take away my hope. I already question that enough myself! Thanks for everything, Izzi
At Tue Jun 10, 05:40:00 PM 2008,
Anonymous said…
I have a question about the safety of Lovenox... for those of you that have already taken it, what were your side effects? I am 30, have a healthy 2 1/2 year old, no problems what so ever with the pregnancy or delivery. My husband and I have been trying to get pregnant over the past year- first miscarriage was a blighted ovum, second pregnancy baby had a heart beat at six weeks, but when the Dr. went back at 8 weeks the heart beat was gone... had blood work done (at my request) and it was discovered I have PAI-1 4G/5g. My factor V and MTHFR were normal. Went to a fertility specialist, he stated that he wasn't sure that the PAI1 was causing the miscarriages b/c a blighted ovum is genetic and he questioned the hormone levels of my second pregnancy as it was so close to my previous miscarriage... As it stands right now, I am 6 weeks and one day pregnant. I have filled my Lovenox prescription, but after reading the warnings in the lovenox box, I am a little freaked out! I am absolutely willing to do just about anything to have another baby, but I admit, I am scared of the lovenox... is this therapy too aggressive since they are not even sure that is what caused the second miscarriage? Or am I just being a big fraidy-cat? Would appreciate any kind of advice or opinions-
Thanks,Anne
At Wed Jun 11, 07:06:00 PM 2008,
Kenneth F. Trofatter, Jr., MD, PhD said…
To Anne June 10: In your circumstances, I too feel it is unlikely that the PAI-1 4G/5G polymorphism caused your based on your previous history and the low risk of this mutation alone. Chromosomal abnormalities are much more likely or some other factor that has yet to be diagnosed. The Lovenox is probably aggressive, but it has been used in 10's of thousands of pregnant women and at prophylactic doses is very safe. If I have marginal indications for placing a patient on it, I will usually discontinue the therapy by 20 weeks. Bets of luck and let us know how things turn out! Dr T
At Thu Jun 12, 11:02:00 AM 2008,
Anonymous said…
Dr. T-
Thank you so much for the response! I decided to go ahead and start the Lovenox, just to be on the safe side, as I was just informed that I am positive for antiphospholipids (forgive me if this is not the correct terminology, this is a lot of information to take in all at once, and I am not too familiar with the terminology) Anyway, I figured the 40mg dose wouldn't hurt anything and like I said, at this point, I am willing to do just about anything for just one more successful pregnancy. I am boggled by all of this, like I said, had an easy pregnancy with my son 2 years ago and then, wham, all kinds of problems... is this a typical manifestation for PAI-1 4G/5G? Since the diagnosis, in January, I have been taking a baby aspirin, prenatal vitamins and a 800 mg tablet of supplemental foic acid, just to be on the safe side. With the second pregnancy, although it ended with a miscarriage, all my hormone levels were right on. Am I safe to assume they will be this time? I requested a blood draw to check progesterone levels for this pregnancy... sorry for all of the questions- is there anything else that I need to do or should be proactive about? Thanks and I look forward to hearing from you- I will keep you posted
Anne
At Sun Jun 15, 09:13:00 AM 2008,
Kenneth F. Trofatter, Jr., MD, PhD said…
To Anne: although you did not tell me the results, I am more concerned about the antiphopholipid antibodies than the PAI-1 polymorphism. If those are abnormal enough, even more aggressive Lovenox therapy might be indicated. Let me know, okay? Dr T
At Mon Jun 16, 06:49:00 AM 2008,
Anonymous said…
Hey Dr T- At the time of my appointment last Tuesday, the Dr. informed me that the antiphospolipids were only "mildly elevated" and very close to normal...unfortunatley, I do not know the quantatative information to give you more insight. I did call my doctor this a.m. and I am waiting to hear back from him... I know he did recheck it last week. I don't really know what else I can do to be proactive in this whole thing, all I can do is pray! But it is a very helpless feeling! I will let you know as soon as I know anything- Anne
At Mon Jun 16, 10:49:00 AM 2008,
Kenneth F. Trofatter, Jr., MD, PhD said…
To Anne: Thanks for letting us know. I know it is nerve-racking, but it sounds like you are in good hands. So, keep the faith and best wishes! Dr T
At Mon Jul 07, 05:42:00 PM 2008,
Anonymous said…
I really hope that someone can gove me some solid insight...I am 31 yrs old and diagnosed with rheumatoid arthritis in January of this year. After unsuccessfully trying for a year to get pregnant, I finally met with RE in Feb. Underwent IUI in March, got pregnant and miscarried at 5 weeks. Was on a 50 mg. subcutaneous shot of Enbrel and 10 mg of prednisone until 2 weeks before my insemination. Decided I would stay on the meds for the next go-around and underwent IUI again in June which did not lead to a pregnancy (although my period was 5 days late). Doc told me today that based on my bloodwork at the beginning of June homozygous for PAI-I and also homozygous for MTHFR (A1298C). He recommended that I take the low dose aspirin and 5 mgs of Folic acid daily. He will check my levels again before they decide on when to do my next IUI. Does this seem aggressive enough to you? Do you recommend that I stay on my Enbrel & prednisone this time? ( I did stay on it for my 2nd IUI). Any advice would be greatly appreciated. Jamie
At Sat Jul 12, 06:36:00 PM 2008,
Kenneth F. Trofatter, Jr., MD, PhD said…
To Jamie: I think staying on that regimen and adding the folic acid and aspirin is certainly reasonable. Did they check to see if you any antiphospholipid antibodies as well? If you are unsuccessful on that regimen, I would empirically add heparin or lovenox the next time. Good luck and thanks for reading. Dr T
At Wed Jul 16, 06:13:00 PM 2008,
Anonymous said…
Dr. T.,
Anonymous October 1, 2007 with an update for you. I decided to try my doctors' recommendation and not use the baby aspirin and just use the Lovenox (for my homozygous PAI-1 and homozygous MTHFR). I had a great pregnancy and just delivered another healthy baby girl! Hooray! I am so glad to have found a regimen that works for me. One doctor suggested that I might be able to discontinue the Lovenox at some point during the pregnancy but this is not an option I am comfortable with. I hope my experience might help someone else. Thank you very much for your time and input! I enjoy reading your blog very much.
At Fri Jul 18, 05:14:00 PM 2008,
Kenneth F. Trofatter, Jr., MD, PhD said…
To anonymous July 16: CONGRATULATIONS! I am so glad things worked out. Thanks for letting us know and for the kind words. Regards, Dr T
At Wed Oct 15, 10:50:00 PM 2008,
Anonymous said…
Hi, all! Have had 2 misc. - both @ 46 yrs old. Am now pregnant @ 48. Taking 200 mg prometrium vag.2x/day.
I don't want another misc! After 2nd misc, had a # of blood tests, incl. aniphospholid anitibodies; don't remember the others, but there was no MTHFR or PA1-1 testing. I can't figure out why. What are these things?
Also, am wondering whether prometrium dose seems OK -- I'm now @ 6 wks -- actually, altho was supposed to be taking beg. day 17, I actualy kind of didn't and really took about an avg. of 175 mg. day until yesterday (when learned was pregnant).
Any info would be much apprec.! I have yet to see a perinatologist!
Also, had U-sound yesterday (5 weeks, 5 days) and they clnd't see anything. I think it's a little early.
I'm not having morning sickness. I'm scared about misc.
Thx!
At Sat Nov 01, 09:28:00 AM 2008,
Kenneth F. Trofatter, Jr., MD, PhD said…
To anonymous Oct 15: Sorry, but I just received your comment in my mailbox. The fact that nothing was seen in your uterus at 6 weeks is not a good sign. the least that should have been there is a gestational sac with a yolk sac and perhaps a visible embryo - even if a heart beat could not be seen. At your age, the risk of having a baby with a chromosomal abnormality in first trimester is 1 in 3 or higher. That is the most likely cause of your early miscarriages although many other factors can also come into play at your age to cause 'infertility'. Please let us know how things turned out and again I am sorry for not getting back to you sooner. Dr T
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