Plasminogen Activator Inhibitor-1 (PAI-1): Role in Adverse Pregnancy Outcome? - 3 - Association with Recurrent Pregnancy Loss
Monday, November 05, 2007
Kenneth F. Trofatter, Jr., MD, PhD
In 1993, Gris and colleagues (J Lab Clin Med 1993;122:606-15) evaluated the fibrinolytic system in 116 women who had recurrent early pregnancy loss (RPL) of unknown etiology matched with a group of 90 women who had never had an early miscarriage. Seventy-four of these 116 women with recurrent losses were found to have at least one abnormal test for fibrinolysis compared to none of the control group. A subgroup of 56 women who were shown to have decreased fibrinolytic activity in blood samples taken from veins that were intentionally occluded were selected for further evaluation. Seventeen of these women produced about half the amount of tissue plasminogen activator (t-PA) compared to the controls, 21 had elevated levels of PAI-1 activity, and 16 had both low t-PA and high PAI-1. Other abnormalities that were found among the RPL women were elevated levels of PAI-2 (like that made by the placenta) in nine and decreased urokinase-like plasminogen activator (u-PA) in six. The bottomline is that with these imbalances in the fibrinolytic system, decreased PA activity and/or increased PAI activity, there would be an increased tendency for blood clots to form and not be broken down. These findings led the authors to conclude that “activators and inhibitors of the fibrinolytic system are frequently abnormal in primary habitual aborters” and that “impaired plasmin dependent proteolysis (fibrin clot breakdown) in women might favor recurrent abortion by promoting fibrin deposition in early placental circulation or by limiting trophoblast development.”
Subsequent studies have supported and extended the findings and conclusions above. In 1999, Glueck and colleagues (Metabolism 1999;48:1589-95) found a significant correlation in women with polycystic ovary syndrome (PCOS) between elevated levels of PAI-1, early pregnancy loss, and no live births. These authors concluded it “is a predominant independent significant positive reversible risk factor for miscarriage in women with PCOS.” In 2003, Dossenabch-Glaninger, et al. (Clin Chem 2003;49:1081-6) evaluated 49 women with a history of two consecutive, or 3 to 6 nonconsecutive, early pregnancy losses compared to 48 women without a history of pregnancy loss for several genetic variants of the coagulation system. They found that homozygosity for PAI-1 or the factor XIII 34 Leu polymorphisms or compound heterozygous status (both of these polymorphisms in the same individual) of these same mutations significantly increased the risk for early pregnancy loss (OR = 2.4; 95% CI, 1.1-5.5).
In our last post, we mentioned that PAI-1 produced by vascular endothelial cells is induced by angiotensin II which is generated by the action of angiotensin I converting enzyme (ACE) and that autoantibodies directed against the angiotensin II type 1 receptor (AT1) found in preeclamptic women was associated with associated with increased production of PAI-1 (Xia, et al., J Soc Gynecol Invest 2003;10:82-93). Along the same lines, Buchholz and colleagues (Hum Reprod 2003;18:2473-7) studied the ACE deletion(D)/insertion(I) and the PAI-1 4G/5G polymorphisms in women with RPL, both of which are associated with increased ACE and PAI-1 expression, respectively. Comparing 184 women with a history of two or more consecutive spontaneous abortions with 127 women who had term pregnancies and no early losses, they found that homozygosity for the D allele of the ACE gene (D/D) was significantly correlated with RPL and the presence of the PAI-1 4G/4G homozygous state further increased PAI-1 levels and risk for early pregnancy loss. As a consequence of these findings, the authors recommended “the incorporation of these two polymorphisms into the spectrum of thrombophilic mutations which should be analyzed in individuals with recurrent spontaneous miscarriages.”
In more recent studies, Glueck and colleagues (Metabolism 2005;54:1345-9) reported that even among women who had had live births, if they had also had a spontaneous abortion, they were at greater risk than women who had never lost a pregnancy for having elevated levels of PAI-1 (33% vs 18%) and for the presence of other aberrations of the coagulation cascade: presence of factor V Leiden homozygosity (15.2% vs 1.6%) and elevated levels of factor VIII (31% vs 18%). These findings carried over to similar observations in women with PCOS (Glueck, et al., Metabolism 2006;55:345-52). In this study they assessed the association of PAI-1 levels in 430 women with PCOS who were divided into the following groups: 1) women who had live births only (n = 208); 2) women who had one or more live births and one or more first trimester losses (n = 111); 3) women who had only had first trimester miscarriages (n = 71). They found that “PAI-1 activity was positively associated with first-trimester miscarriage (p = 0.004)” … and “for each 5 IU/mL increment in PAI-1 activity, the risk being in an adverse first-trimester miscarriage …increased (OR, 1.12; 95% CI, 1.04-1.20).” In the same study, they also evaluated the association of the PAI-1 4G polymorphism in 921 women with PCOS compared to 126 normal females and again demonstrated (although the difference was not as dramatic in these women with a more heterogeneous obstetrical history – 78% in the PCOS group compared to 69% in controls) the 4G allele “is more common in women with PCOS than in normal women and, in concert with obesity, hyperinsulinemia, and hypertriglyceridemia, contributes to treatable, hypofibrinolytic, miscarriage-promoting, high PAI-1 activity.”
Coulam and colleagues (Reprod Biomed Online 2006;12:322-7) compared the prevalence of ten thrombophilic gene mutations in 42 women with a history of recurrent implantation failure after IVF embryo transfer with 20 fertile women. They found that the women with implantation failure had a significantly higher prevalence of PAI-1 4G/5G polymorphisms than controls (P = 0.007). Although they found no significant differences in the prevalence of any other single gene mutation, they did find “the prevalence of total gene mutations among patients with implantation failure was significantly higher than among controls. More than 3 gene mutations among the 10 genes studied were observed in 74% of women with implantation failure” compared to 20% of controls (P = 0.0004). They “concluded that inherited thrombophilias are associated with implantation failure” and this highly significant “association is manifest by totatl number of mutations as well as with PAI-1 mutations.”
Using the same approach, Coulam’s group also reported (Am J Reprod Immunol 2006;55:360-5) a comparison between 150 women with two or more recurrent pregnancy losses and 20 fertile women with no history of pregnancy losses. In this study they also found that there were “no differences in the frequency of specific gene mutations…however, the prevalence of homozygous mutations (59% vs 10%) and total gene mutations among patients with recurrent miscarriage was significantly higher than among controls.” As in their previous report, more than 3 mutations among the 10 genes studied were observed in a significantly higher percentage of women with recurrent miscarriage than controls (68% vs 21%). Subsequently, they reported on 550 women with RPL and among the polymorphisms they investigated they found that PAI-1 4G/5G (P = 0.009), factor XIII V34L (P < 0.0001), and homozygous MTHFR C677T (P < 0.0001) correlated significantly with RPL compared to controls.
To summarize today’s post, despite the heterogeneity of findings detailed in the studies referenced above, there seems to be a common thread: recurrent pregnancy loss, in the absence of other explanations (e.g., chromosomal abnormalities, uterine anomalies, chronic maternal disease) is frequently accompanied by imbalances in the fibrinolytic system. These imbalances are uniformly those that lead, theoretically, to decreased fibrinolysis and may include genetic defects of the coagulation system and are frequently accompanied by conditions that lead to increased production of PAI-1. The mechanism by which these factors might actually contribute to an increased risk for recurrent early pregnancy loss will be discussed in the next post…
Labels: fibrinolysis, PAI-1, recurrent pregnancy loss
35 Comments:
At Mon Nov 05, 09:46:00 PM 2007,
Anonymous said…
Hi Dr. Trofatter,
thanks for posting information i can finally understand about PAI-1.
i have had 2 pregnancy losses, first one was a spontaneous AB in Jan 2004 definitely within 4-5 weeks of conception (did not reach the point of seeing an OB-GYN) and the second one was a D&C for missed AB in Aug 07 within 8-9 weeks. my OB-GYN subsequently ordered tests for me and i have the following abnormal results:
Heterozygosity for A1298C mutation
One copy of 4G allele in PAI-1 gene
Positive result for anti-nuclear AB but negative result on the titre(1:40)
Protein S antigen result: 163 H
PTT-LA result: 42 H
Fetal Tissue testing showed that all chromosomes were structurally normal.
My OB-GYN is currently on vacation but she left me a message saying i needed a high-risk consult which i am following up on. However, I can't find any information on the internet about what these results mean in combination. i'm not even sure what all these things mean.
I hope you can help me with this. can i begin trying to conceive again or should i wait to see the high risk OB-GYN first? is there a possibility of the baby having a serious disorder of some kind or should i forget about having children?
thanks!
At Tue Nov 13, 04:48:00 PM 2007,
Kenneth F. Trofatter, Jr., MD, PhD said…
To Anonymous Nov 5: At this point, try not to get overly stressed out about your test results. Many women carry one dose (heterozygotes) for the MTHFR A1298C and PAI-1 4G polymorphisms and have no trouble at all with pregnancy. Many women also have a slight positive antinuclear antibody titer. I am not worried about the protein S level at all - it's deficiencies of protein S that lead to 'thrombophilia'. The lupus anticoagulant is only modestly abnormal and might not even be there if the test is carefully repeated (that's one test that is easy to mess up if the blood sample isn't handled just right). So far, I don't see anything a baby aspirin, a prenatal vitamin, and extra folic acid might not just help! In other words, your two losses might not be realated to any of those things! By the way, what other tests did they do? Anyone who counsels you is going to want to know a few other things such as...Did you have any trouble getting pregnant? Was the father of the most recent miscarriage the same as that of your first? Medical problems? Family history?, etc.. At this point you do not appear to be at any great risk for serious complications for you or a baby so I am NOT ready to tell you to "forget about having a baby"!!! Good luck and thanks for reading. Dr T
At Sat Dec 08, 11:25:00 PM 2007,
ameliarose said…
Hello Dr. Trofater-Thank you for your post. Ironically, I was one of your residents. I am homozygote for the following three: PA-I, factor XIII and factor VIII. Over last 26 months, I had 2 SAB (nl karytypes-on no lovenox); followed by 31 week PTD (no IUGR)-on baby aspirin and lovenox (also complicated by short CL and PTL-started terbutaline pump and weekly progesterone at around 20 weeks); followed by 3rd SAB; and now am 9 weeks with 5th pregnancy on baby asiprin and once daily lovenox. Now I have been instructed to stop both aspirin and lovenox, besides also hearing no tocolytics less than 23 weeks here. And did I mention I also have bicornuate uterus. What are your thoughts regarding anticoagulation if any for me? RPL secondary to bicornuate? Looking forward to hear your opinions and expertise. Thanks.
At Thu Dec 13, 12:00:00 PM 2007,
Kenneth F. Trofatter, Jr., MD, PhD said…
To AmeliaRose Dec 8: Hi there girl. You have had a rough time of it haven't you. I know what our REI folks would say - fix the bicornuate uterus. They swear it leads to recurrent early pregnancy loss, although the mechanism of that is still a little unclear to me. Some say "poor blood supply, other subclinical endometriosis. There is NO DOUBT though, it also leads to cervical incompetence and with you history of short cervix, premature labor, and early delivery, cerclage should definitely be considered in your case once you've gotten through first trimester. Don't let then talk you out of that just because you had "preterm contractions" with your last pregnancy. The primary benefit of progesterone therapy in midtrimester seems to be in those individuals with a short cervix, so I would definitely include that in your treatment regimen as well. As for the Lovenox and aspirin - it's hard to say. My suggestion probably would be to take those as well and stop the lovenox before 20weeks (or anytime after first trimester). There is no RIGHT answer here - much is witchcraft! By the way, do you have any other medical problems we need to be concerned about at this point? Ovulatory dysfunction, thyroid disease, diabetes? Thanks for reading and take care of yourself! Dr T
At Fri Dec 14, 07:43:00 AM 2007,
chucksusanb said…
Dr. T,
I had one successful pregnancy and my daughter is 4 years old. I have +ANA, +ACA and MTHFR 1298C hetero gene. I took one baby aspirin, and prenatals during my pregnancy.
Last year I had one very early miscarriage @ 4.5 weeks.
I am now pregnant again, my Dr wants me on Innohep, Folgard 2.2mg and prenatals.
I feel more comfortable just taking one baby aspirin, folgard 2.2 and prenatals.
Am I putting myself at risk by not taking Innohep injections (low molecular weight heparin)? I am 38 years old.
Thanks sincerely,
Susan
At Fri Dec 14, 07:46:00 AM 2007,
Chuck Susan and Grace said…
Dr. T,
I had one successful pregnancy and my daughter is 4 years old. I have ANA, ACA and MTHFR 1298C hetero gene. I took one baby aspirin, and prenatals during my pregnancy.
Last year I had one very early miscarriage at 4.5 weeks.
I am now pregnant again, my Dr wants me on Innohep, Folgard 2.2mg and prenatals.
I feel more comfortable just taking one baby aspirin, folgard 2.2 and prenatals.
Am I putting myself at risk by not taking Innohep injections (low molecular weight heparin)? I am 38 years old.
Thanks most sincerely,
Susan
At Fri Dec 14, 06:35:00 PM 2007,
Kenneth F. Trofatter, Jr., MD, PhD said…
To Susan Dec 14: The first thing I need to know is why you had those studies done? What type titer of anticardiolipin antibodies were found? Were they done because of the miscarriage or have you had (or is there a family history of) blood clotting problems? Do you have an autoimmune condition or any other medical problems? Why were you on aspirin during your other pregnancy and did you have any complications with that pregnancy? With that information in hand, I will be in a better position to answer your question regarding risk and treatement! Thanks for reading! Dr T
At Mon Dec 17, 09:07:00 AM 2007,
Susan said…
Dr T
Thanks for responding to my questions. I will now answer yours.
I had these studies done because of my known ANA. I was having some numbness, dizziness about 10 years ago. For this reason, they tested me for that. I have had no problems related to the ANA though since.
ACA titers were 15
The ANA, ACA & MTHFR and others (which were normal) were just some random immunological testing they did (since they knew I had +ANA).
I have two Aunts (my Dads side) who have had strokes. One Aunt had hers at age 50 and the other at 70.
I was on baby aspirin with my daughter (who is now 4) because of the +ANA and +ACA. I did great with that.
Recent blood work from last year showed I have MTHFR hetero gene.
I'm just wondering if baby aspirin, Folgard, Lipil (omega 3 fatty acid) and prenatals would be sufficient? Or is LMWH (low molecular weight heparin) really necessary?
Thank you kindly Dr. T for taking the time to respond. I've enjoyed reading your articles.
Most Sincerely,
Susan
At Mon Dec 17, 12:27:00 PM 2007,
Kenneth F. Trofatter, Jr., MD, PhD said…
To Susan Dec 17: It's up to you! Personally, if you have only had one miscarriage and did well on the regimen without heparin in your previous pregnancy, I think that is a reasonable route to take. From what you have told me, I probably would not have even offered you the heparin unless you begged me to give it to you - and then I would only use low-dose 'prophylactic' (rather than therapeutic) regimen. Good luck to you and let us know how things turn out. Dr T
At Sun Dec 23, 09:43:00 AM 2007,
Susan said…
Thanks Dr. To to your comments/answers to my question. I just found out I am pregnant with TWINS. Would this change your opinion as to whether or not I should be on Innohep or aspirin alone? I see the Maternal Fetal Medicine Dr next week, but I really wanted another opinion from a Maternal Fetal Medicine Physician as well. Thanks once again most kindly. And have a very happy holiday season!
Susan
At Fri Jan 04, 06:56:00 PM 2008,
Kenneth F. Trofatter, Jr., MD, PhD said…
To Susan Dec 23: I apologize for not answering until today, by=ut Healthline has had some 'technical difficulties' and I just got your note (Jan 4). OMG, TWINS! Well congratulations, and no, my original recommendation still holds. Good luck to you and let us know how things turn out! Dr T
At Tue Jan 15, 09:15:00 AM 2008,
Julia said…
I am thrilled to find all of your PAI-1/miscarriage posts as these are new since I searched the internet in October. I have had the following pregnancy history (1 DD, 1 stillbirth, 4 miscarriages, 2 chem pg)
Nov 02 - Blighted ovum (growth to 5w) no HB
Jan 04 - Healthy Daughter now 4
Feb 06 - Stillborn girl at 36.5 w due to compressed umbilical cord around her body
Aug 06 - Blighted ovum (growth to 6w) no HB
Sep 06 - RLP testing shows PAI-1 level of 136 (very, very high) & IGM level of 28 (slightly high)
Treatment - prenatal vit, baby asprin, Folgard when TTCing, Lovenox after testing +PG
Oct 06 - PAI-1 4G/5G variation determined
Dec 06 - Miscarriage - saw HB but stopped at 10w - suspected genetic problem
Apr 07 - Miscarriage - saw HB but stopped at 9w - triploidy DNA
July 07 - Chem Pg
Aug 07 - Chem Pg
Oct 07 - Tried IVF cycle but my body did not absorb HCG trigger shot correctly (not enough in my system), eggs didn't mature even though there were 20+ underway so the IVF cycle was scrapped.
My RE did a lot of blood tests (25 or so) and the PAI-1 was the only one that turned up. Have been tested for PCOS but have never tested positive.
- Is there anything else I should test for?
- I'm taking the baby asprin, folgard & prenatal right now for an IVF cycle we hope to start at the end of February - is that what you would recommend.
- In light of an IVF cycle with my PAI-1 diagnosis is there anything else you would recommend to do to help with egg quality, implantation, etc?
Thanks for your help-
Julia
At Wed Jan 16, 08:50:00 PM 2008,
Kenneth F. Trofatter, Jr., MD, PhD said…
Julia, with that high level of PAI-1, you might still be relatively 'insulin resistant' even if you don't meet criteria for PCOS. They might consider adding metformin to the mix for a couple of months before trying to get pregnant. Otherwise, the therapeutic approach sounds good to me at this point. Best of luck. Dr T
At Thu Feb 07, 08:32:00 PM 2008,
Julia said…
Thank you for your info. I went and had my fasting insulin tested and it came back at 6 (normal is 6-25) and so that is fine.
But on Cd8 with my new RE he counted 36 antral follicles and called my ovaries "PCOS-like" even though I don't have any of the other typical PCOS symptoms. This new RE put me on METFORMIN XR and I will have about 2 months on it before our next IVF. I'm so glad he put me on it conservatively because we are so tired of miscarriages and the clock is ticking LOUDLY.
You have such a wealth of info on these pages - I just wish I had found them much sooner!
At Fri Feb 08, 07:34:00 PM 2008,
chucksusanandgrace said…
Dr. T,
You wanted me to let you know how my twin pregnancy turned out. Unfortunately, I lost both of the twins @ 10 weeks. Went in for another ultrasound and both had stopped growing. I just wanted to let you know. I do appreciate your help and information. I decided not to take the low molecular weight heperin injections. I'm thinking this was a chromosome issue, although I am now done trying to conceive altogether.
Once again, I appreciate the advice you have given us.
Susan
At Sat Feb 09, 07:36:00 PM 2008,
Kenneth F. Trofatter, Jr., MD, PhD said…
To Julia Feb 7: Sounds like a reasonable plan. Let us know how you do, okay? Again, best of luck to you! Dr T
At Mon Feb 11, 09:44:00 AM 2008,
Amy said…
I had a successful full term pregnancy in 2004 that was complicated by preeclampsia. I was induced at 38 weeks for raised BP and some protein found at week 36 (but not week 38) -- 7 days post partum I had BP of 202/115 (no protein)and was given IV BP meds to bring it down. I took oral medication for about 16 weeks postpartum. When considering entering another pregnancy, I had many tests run to look for underlying disorders which may have caused this post partum situation:
PT was 10, INR .7
Factor VIII was normal
TSH was normal
ANA was negative
Factor V was negative
Homocysteine was normal
Protein S was normal
Antithrombin III was normal
Protein C was normal
I was also told that I am PAI 4G/5G.
I entered another pregnancy and upon confirming the pregnancy with a HPT, I began a daily dose of LDA. I was also taking prenatal, omega 3, and calcium with Vitamin D.
According to ultrasound, that pregnancy stopped progressing early (less that 5 weeks), and I miscarried at about 6.5 weeks.
And now, finally -- my questions!
Do you think the PAI 4G/5G caused either the PE or the early miscarriage? If so, what regimin of medication would you recommend? Would you recommend any further testing? And do you think it is a good or bad idea for me to enter into another pregnancy?
At Thu Feb 14, 08:32:00 PM 2008,
Kenneth F. Trofatter, Jr., MD, PhD said…
To Amy Feb 11: I am curious... was the baby you carried normal weight or growth-restricted? Two tests conspicuously absent from your list are lupus anticoagulant and anticardiolipin or antiphospholipid antibodies? Is there any family history or recurrent early pregnancy loss, severe preeclampsia, automimmune disorders? To answer your question, I doubt the PAI-1 4G/5G polymorphism alone set you up for your problems, but it may have contributed to the outcomes given the right 'cofactor(s)'. Let me know about my questions and I will see if I have any other thoughts. Thanks for reading! Dr T
At Thu Feb 14, 08:51:00 PM 2008,
Kenneth F. Trofatter, Jr., MD, PhD said…
To Susan Feb 8: I am so sorry Susan. Please stay in touch with us. Dr T
At Mon Feb 25, 03:53:00 PM 2008,
Amy said…
I had the APA panel come back normal, so it looks like all I'm dealing with is the PAI 4G/5G polymorphism.
Any thoughts on what I should try going forward?
At Mon Feb 25, 04:43:00 PM 2008,
Anonymous said…
Dr. T,
I'm 34. I had a miscarriage at about 12 weeks many years ago. About one year ago, we began trying to conceive through artificial insemination. I had one insemination with no result, followed by two chemical pregnancies two months apart. The first terminated just after implantation, and the second at close to 6 weeks, though my hormones had been doubling normally and everything had seemed fine.
My doctor did a battery of blood tests and found out I am:
-heterozygous for MTHFR C677T and A1298C
-negative for Leiden V, and some other mutations, (he checked 7 mutations in total, though he did not test for PAI)
-normal APL
-slightly elevated CRP
-normal homocystein
I have severe Rheumatoid Arthritis. On advice from my rheumatologist, I stopped my methotrexate six months prior to trying to conceive and my etanercept and a.s.a. three months prior. My disease was not well controlled, and I had lots of inflammation. My family history has autoimmune disease and stroke...my mother has lupus, type II diabetes and history of miscarriages and stillbirth.
When my doctor found my MTHFR mutations, he recommended 81 mg aspirin daily, 1 mg of folic acid beginning prior to conception, plus heparin injections to begin at conception. Based on my own reading, I have increased my folic acid to 5 mg daily and begun taking B6 and B12 vitamins as well.
After some research, I discovered that I could do a pregnancy while taking etanercept and have now been back on it for 1.5 months, with now good control of my rheumatoid arthritis inflammation and now normal CRP and sed rate.
I am looking at having another insemination soon, and my doctor now wonders if I should wait, while he tests for PAI-1 which he did not have access to before.
I guess I want to know:
Should I test for PAI-1? If the therapy is the same as for MTHFR, will it help any decision-making to add this to my list?
How long will it take for my folic acid and vitamins to take effect...I have been on them a few weeks...should I longer before trying to conceive to bring my folate levels up more?
Could inflammation from my RA be playing a role in my recurring miscarriage problem?
Thanks,
J
At Wed Feb 27, 05:38:00 PM 2008,
Kenneth F. Trofatter, Jr., MD, PhD said…
To J Feb 25: I don't think knowing your PAI-1 level is going to affect your treatment one way or the other. You have been on the vitamins long enough to derive any benefit they might offer as well. Anyone with the family history and personal history you relate has an underlying imbalance in their immune response that is probablt the primary cause of your 'infertility.' I do not know enough about the use of etanercept (tumor necrosis factor-alpha) and pregnancy. Some immunosuppressive drugs may actually HELP you carry a pregnancy past first trimester, but in this case I do not know. I would suggest that your doctor use either heparin or low-molecular-weight heparin at THERAPEUTIC (not prophylactic) dosages. Since in your case, we really do not know what we are treating, if another pregnancy attempt fails, your doctor should consider Prednisone therapy to the regimen as well. I will be VERY interested to know how things turn out in your case, so please stay in touch! Dr T
At Thu Mar 13, 07:49:00 PM 2008,
Anonymous said…
I don't know how to put this, forgive me. I am up to now 44 losses & I am only 36yrs old. In 2005 I finaly got a doctor that would listin to me & not look at me like I was nuts. All of this seems like a lot to take in. I'm only on 81mg aspirin & folic acid, till I think I may be pregnant, then heprin twice a day. I think I should be on more than that, it's not working. The more I read others know more than I do stats & so on, Do I need to push more to get the answers from the doctor or am I not asking the right questions?
At Wed Mar 19, 06:23:00 PM 2008,
Kenneth F. Trofatter, Jr., MD, PhD said…
To Anonymous Mar 13: That would certainly be a reasonable approach to empiric therapy for recurrent pregnancy losses, but I would be more interested in knowing what sort of evaluation you have had to date for all those losses and by what sort of doctor(s)! You may need to be seeing a specialist in Reproductive Endocrinology if you haven't already. Dr T
At Wed Jun 11, 08:38:00 AM 2008,
Amy L. said…
Dr. T,
I don't know if you're still checking this thread or not, but I wanted to answer the questions you had asked me back in Feb in response to my original question about PAI 1 and preelcampsia. I had the lupus anticoagulant and antiphospholipid antibodies tested and it all came back normal. My son that was born in 2004 was not growth restricted - at 38 weeks, he was born weighing 7lbs 2oz. I am now 13 weeks pregnant and am taking low dose aspirin, calcium with vitamin D, prenatals, and omega 3 supplements. So far, my blood pressure is fine, and baby's growth is right on track (by ultrasound). What do you think my odds are for a healthy pregnancy this time around? Any other things you think I should be trying?
Amy
At Wed Jun 11, 07:11:00 PM 2008,
Kenneth F. Trofatter, Jr., MD, PhD said…
To Amy L: Yep, I respond to comments on all my posts, regardless of when they were written - and sometimes it is hard to keep up. Regardless, congratulations on your pregnancy. I don't think I would change anything you are doing right now. Good luck and thanks for checking back with us! Dr T
At Tue Jul 08, 09:19:00 AM 2008,
Anonymous said…
Dr. Trofatter,
Thanks for all the helpful information. I am 30 years old and have suffered from 3 early pregnancy losses. All have been within 6-8 week gestation. I have been going to a RE prior the last loss. He did a complete blood work up before we concieved the last loss, which was 2 weeks ago (7 week gestation). My husband and I have a normal karyotype. It was discovered that I have several mutations: heterozygous MTHFR 677CT, heterozygous MTHFR 1298AC, heterozygous PAI-1 5G/4G, heterozygous Factor XIII V34L, and 155% elevation of Factor VIII. The RE put me on folic acid, 81 mg aspirin, prenatal vitamins, and progesterone during this last loss. I was concerned about all my genetic abnormalities and consulted with a hematologist. He suggested that I receive Lovenox, but the RE said he would not try this treatment until after another misscarry. What kind of reasoning is that? He is convinced that I am having recurrent pregnancy loss due to fetus genetic abnormalities, so I had a D&C two weeks ago and the results for the fetus won't be back for another 4 weeks. Could my losses be due to the combination of my mutations causing increased thrombosis? Isn't the increased factor VIII causing increased thrombosis? Should Lovenox be used in the next pregnancy? If so, how early?
At Wed Jul 09, 11:52:00 AM 2008,
Julia said…
I'm Julia and I just wanted to follow up from my January 15th post.
I had suffered from 5 miscarriages in a row and my old RE had put me on lovenox, baby asprin & folgard due to having the PAI-1 4G/5G mutation. My new RE also added metformin XR in January 2008.
In April 08 we went through an IVF cycle (with genetic testing) and I'm now PREGNANT WITH TWINS and am 12 weeks along and the babies are doing really well! I'm still on all 4 meds right now!
Thank you so much for your help on this board!
At Sat Jul 12, 05:11:00 PM 2008,
Kenneth F. Trofatter, Jr., MD, PhD said…
To anonymous July 8: It is difficult enough to sort out the effects of one abnormality on pregnancy loss - ao when ther is a COMBINATION of abnormalities to deal with, we are all just plain stupid. You have proven you have difficulty carrying pregnancies through first trimester. If the last baby is chromosomally normal, I would suggest pushing for the lovenox and would start that during the mid luteal phase or as soon as a pregnancy is confirmed chemically. It is more likely to help than hurt! Good luck to you. Dr T
At Sat Jul 12, 05:13:00 PM 2008,
Kenneth F. Trofatter, Jr., MD, PhD said…
To Julia: Well, CONGRATULATIONS! Let us know how things turn out. Make sure they look at your cervix by ultrasound at 20 weeks! Dr T
At Tue Jul 15, 10:50:00 PM 2008,
ND said…
Hello Dr,
I had a pregnancy which seemed to be going normal till around 24th week when pre-eclampsia was discovered. I delivered in 25th week (Feb'08) and baby could survive for 2 week only. I was on BP medication for almost 6 weeks after delivery and now my BP has returned to normal. They also performed Thrombophilia profile. The results indicated elevated levels of Homocysteine (16.2), elevated protein S activity (141) and elevated PAI-1 (131). I was referred to hematologist for treating these issues. The hematologist was not sure about the levels being elevated due to pregnacy/pre-eclampsia or if the levels are high naturally. So he recommended waiting for 3 months and then doing the thrombophilia profile again. The second profiling will be done in August. Are these elevated levels related to the occurance of pre-eclampsia and how are my prospects for future successful pregnancy?
Thanks,
At Wed Jul 16, 08:03:00 PM 2008,
Anonymous said…
Hi Dr. T.,
I am 27 years old and have had 2healthy, full term 8 pound babies now 3 and 5. Last year at 17 weeks, I went in for a check up and there were no fetal heart tones. The autopsy revealed the baby was normal. Upon referral to a MFM doctor, I just learned that I have two thrombophilias: heterozygous for MTHFR and homo for PAI-1. I am now 20 weeks pregnant. Ultrasound at 18 weeks showed baby girl is appropriate size for date and appears healthy. I am on baby aspirin and Heparin 7500 units BID. Is the Heparin really necessary in your opinion. Why the two great pregnancies before? Was that just luck or age? Thanks!
At Fri Jul 18, 04:43:00 PM 2008,
Kenneth F. Trofatter, Jr., MD, PhD said…
To ND: Do you know what other tests were included in the "thrombophilia profile" and was that done while you were hospitalized with the preeclampsia? I am still not sure we have the answer for your severe preeclampsia based on these studies, although I am concerned about the elevated homocysteine level. At this point, it is probably best to repeat the studies as suggested by the hematologist. Sorry I cannot be of more help at this time, but please let us know the results. Dr T
At Fri Jul 18, 04:49:00 PM 2008,
Kenneth F. Trofatter, Jr., MD, PhD said…
To anonymous July 16: I must agree with you. I am not sure those genetic polymorphisms are the cause of the loss of your other baby. In cases like yours with borderline indications for heparin (and in view of your prior successful pregnancy outcomes), at this point in the pregnancy, I would offer to stop the heparin. It has probably done any good it was going to with regard to placental development. Best wishes and let us know how things turn out. Dr T
At Tue Jul 22, 11:01:00 PM 2008,
Neelima said…
Hi Dr
The other test performed about Thrombophilia profile are as follows:
1) Cardiolipin IgG: <15(Normal)
2) Cardiolipin IgM: <12(Normal)
3) Factor V Leiden Mutation: -ve(Normal)
4) Prothrombin Gene Mutation: -ve(Normal)
5) Protein C Antigen: 101(Normal)
6) Protein S Antigen, Free: 140(Normal)
7) Protein S Antigen, Total: 119(Normal)
8) Protein C Activity: 145(Normal)
9) Protein S Activity: 141(High)
10) Antithrombin III Activity: 101(Normal)
11) Lupus Anticoagulant: No evidence detected
12) PAI-1: 131(High)
13) Homocysteine: 16.2(High)
14) MTHFR DNA MUTATION: +ve for one copy of A1298C Mutation and -ve for C677T mutation.
Can the level of Homocysteines be lowered by extra b vitamins and folate therapy ?
Can I be able to carry pregnancy again with baby aspirin ,calcium(1000mg) and heparin along with proper monitoring by perinatoligists ?
Thanks,
ND
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