Hughes Syndrome

The search for an explanation of my losses and other pregnancy problems has always led to two theories: 1) a blood clotting disorder or 2) a genetic issue. The genetics theory is discussed here.

Since my recent visit with the perinatologist, I've been wondering more about the clotting theory. As I posted previously, there are some clues that this might be the case but my lab test results don't fit neatly into the diagnostic criteria. To get an official diagnosis one has to exhibit certain symptoms AND have conclusive positive lab tests. Here are the symptoms of the clotting disorder Hughes Syndrome (a.k.a. antiphospholipid antibody syndrome) and whether I have them:

Blood Clots that cause "young" stroke or heart attack (under age 45), pulmonary embolism (clot in lung), or deep vein thrombosis (usually in the leg).

I've had none of these (yay!). There's no family history of this either. The only clot problem I've ever had was a *blush* debilitating thrombosed hemorrhoid following my first child's birth. According to my doctors, this clot does not count. I can tell you, though, that the indignity of stirrups is nothing compared to the humiliation of butt surgery done under only local anesthesia.  Moving on . . .

Pregnancy problems -
Intra-uterine growth resriction (IUGR) - Yes, my first child had this
Placental abruption - Partial abruption was suspected during labor with my second child, but it was never confirmed
Miscarriage, particularly in mid-pregnancy - A big YES on that one
Pre-eclampsia - No
Infertility - yes

Memory loss - My memory has not been great in recent years, but it's improved since this. I've always attributed it to trauma, inadequate sleep, anxiety, and all the drugs I've been on. My kids never let me forget that I'm "not a good rememberer"!

Headaches, especially migraines - I've never been one to get a lot of bad headaches but lately I've noticed subtle headaches practically every day. They rarely interfere with my normal activities. I suspect (and hope!) they're caused by stress, anxiety, etc and not by tiny blood clots in my brain!

Cold skin - I seem to have poor circulation in my hands and feet compared with most people. I've noticed my feet sometimes turn purple (but aren't uncomfortable) when I stand in one position for 15 minutes or so. Also my hands are like ice all winter even if I'm indoors all day. I noticed this long before I ever tried having babies, but I never thought for a moment that having icy hands could be a harbinger of doom!

Purple-blue discoloration of the skin, particularly around the knees and elbows - I've noticed this around my knees sometimes after showering.

Shortly after my losses I mentioned these supposed signs to my doctor and he dismissed them as "grasping at straws". As a result, I haven't brought it up again with subsequent doctors, but maybe there is something significant here after all.

Other than the pregnancy issues, most of the symptoms I have could easily be dismissed as subtle or subjective. I mean, everyone gets headaches. Everyone forgets things. Everyone gets cold, especially here in Minnesota! How do you know when you're outside the normal zone?

If thrombophilia (too much clotting) IS my problem, then there may be hope for me assuming I can ever actually get pregnant. According to several studies, Hughes Syndrome patients' odds of successful pregnancy are about 20% without treatment.  My success rate thus far is 40% - lucky me!  With aspirin and heparin treatment it goes up to about 80%. I'd love to give heparin a shot! Now if I could just get pregnant . . .

More Answers or Just More Questions?

First, my daughter Tania's artwork is featured on Still Life 365 today! 

Now down to business.  Today I finally got the clinic notes from the perinatology consult I had earlier this month.  To my surprise the blood tests actually yielded some interesting results, however this does little to clarify why my pregnancy history is so tragic or whether there's any hope for the future.  I'll spare you the life-threateningly boring science lesson about clotting disorders and just link to the heavy scientific explanations.  If you want to make your head explode, go ahead and try to understand this stuff.  Here are the results from my perinatology consult:

ANA (antinuclear antibody) – Positive 1:40 with speckled pattern
Apparently this is a low positive, so there's absolutely nothing definitive about it.  Just another positive result that makes doctors go "hmm", but not "AHA, now we know what's wrong with you".

Beta 2 Glycoprotein 1 -
IgA: 69.46 U/mL
IgM: 4.84 U/mL
IgG: 3.72 U/mL

Note from Mayo Clinic Lab for IgA, IgM, and IgG interpretation:
10.0 U/mL or less = negative
10.0 – 14.9 U/mL = borderline
Greater than 15 U/mL = positive

If IgM or IgG is positive, the diagnosis would be antiphospholipid antibody syndrome (a.k.a. Hughes Syndrome, which is certainly easier to say).  Only my IgA is very elevated and (surprise!) there is not adequate research to indicate what this means.  Again - "HMM" a little louder this time, but NOT "AHA!!".

In 2007 just after my first loss I tested positive for Anti-cardiolipin antibodies.  Results from testing immediately after delivery showed a "Moderate Positive" for IgG, followed by retesting the following month which showed an "Inconclusive" level.  Tests for IgM were negative.  Positive IgM levels indicate a problem.  Positive IgG levels - well, no one's really sure exactly what that means.  Hmm - not AHA.  Are you seeing a pattern here?

Subsequent Anticardiolipin testing has been completely negative both after losing Miles (July 2007) and now (September 2010).  As if things needed to be any more unclear, results on all of these tests are transient - you can test positive and then test again later and be negative.  Or vice versa.

Additionally, I am heterozygous for MTHFT mutation C677T.  This means I have one copy of the gene.  The significance of this, as you may have guessed, is unclear.  Hmmm. If I were homozygous (two copies of the gene) then it would be clinically significant. 

So those are all the answers I've gotten from 40+ vials of blood, not to mention buckets of tears. I never expected any definitive answers about my horrible pregnancies from the perinatologist.  Indeed, I'm convinced that there's not a single person anywhere in the world who can give me solid answers.  Still, it's depressing to hear yet again that there is no certain explanation for my losses and no clear way to prevent it from happening again (other than remaining Super Infertile!). 

I've been reading more about Hughes Syndrome and I do fit a lot of the descriptions.   This post is getting pretty long, though, so we'll get into that later.  Sorry to keep you on the edge of your seat!  Seriously though, this blog is meant for the poor souls who will inevitably follow in my unlucky footsteps so we have to get into boring clinical stuff from time to time.

Even More Injections! HOORAY!!

Today was my visit with the perinatologist.  This was the third doctor with whom I've discussed starting Lovenox from embryo transfer. The other two said no. I've been doctor shopping for drugs! Whatever it takes, I guess. My great news is that this perinatologist IS on board with the idea of allowing me to start Lovenox from embryo transfer rather than waiting for a (hopefully) positive pregnancy test. She emphasized that there's no research for or against doing this. I assured her that I know all too well that there's practically no research on anything related to my situation. I just want to give this my best shot!  I'm rejoicing because I get to give myself even more injections. I can't believe this is my life.

The perinatologist also ordered a whole lot of blood tests on me.  Many are repeats of thrombophilia tests I had three years ago because she says results can change over time.  My blood is headed to the Mayo clinic and it'll take at least a week for results.  This is just to see if we can find more clues, not to determine whether Lovenox is indicated or not.  Regardless of the results, she said she would definitely prescribe it based on my history.  She also said to take additional supplements - Omega 3, Vitamin D, and a massive amount of folic acid.

Next week is the nurses consult for my next IVF cycle and also a wanding to check for cysts.  In addition to today's appointment, I also had to visit a doctor last week.   These last two appointments felt very strange because I got to keep my pants on!  Of course it would have been even stranger if I didn't have my pants on, since one appointment was for an ear problem! 

The Lovenox Dilemma

I posted before about my Lovenox dilemma: whether to start it now or wait until there are (hopefully) rising betas. Quite a few people shared their experiences and comments, so I thought I'd write about how it all shook out. I called the perinatologist and she said she wouldn't prescribe Lovenox until rising betas, which is what my RE had said. With my terrible pregnancy history, this makes me nervous, especially since I know a lot of doctors have patients start from transfer or earlier if they're doing IVF.

Of course if I'm not able to get pregnant even with IVF then it is not an issue, but in optimistic moments when I think I really could get pregnant, I've wondered about getting some Lovenox on the black market and using it before the pregnancy test. It is easy to do, but that option would also would make me very nervous, especially in light of the fact that prescription drugs may have played a role in two of my siblings' deaths.

It sounds morbid, but my sons' deaths pull me in one direction on the Lovenox dilemma

and my siblings' deaths pull me in the other direction.

If I could get the drug from a doctor or even just someone I know and trust, I would do it. Getting it from a total stranger is just too risky not only because it may have been improperly stored, but also because Lovenox is an expensive drug and there is more incentive for unscrupulous people to try selling expired, damaged, or even counterfeit Lovenox. I just can't go there. For now, all I can do is make sure to take baby aspirin religiously. So that's where I am on the Lovenox question and I hope I won't regret it.

Right now I'm just hoping for happiness ahead and also missing these four people that I love. They all died young, tragically, and very suddenly - there was no time for goodbye. In the cases of my sons, there was no time for hello either. Is it any wonder I want so desperately for my weeping to be turned into dancing by bringing home a rainbow baby?

In Which the Anxiety Level Goes Up a Notch

I posted last week about my attempts to get my RE to start me on Lovenox at transfer rather than waiting for rising betas. With my history I want to give this my very best shot (ha!), but she has officially refused my third desperate plea. Three strikes and I’m out. I don’t see any way to prevail on this one.

She sent me an article saying heparin didn’t improve outcomes [Aspirin plus Heparin or Aspirin Alone in Women with Recurrent Miscarriage; New England Journal of Medicine; March 24, 2010] but as this article notes, there are all kinds of conflicting studies on this. Even though the cause of my pregnancy issues is unclear, I felt like we have enough clues here to justify aggressive action:

First Loss - Jeremiah (January 2007 at 21w 3d) cord hypercoiling

Moderate positive result on anticardiolipin antibody IgG; after six weeks this was retested and the level was "inconclusive"

From Pathology: “Received is placenta, umbilical cord, and fragments of blood clot and decidual tissue. Twisting of the cord appears abnormal, with more twists per centimeter than average. The placenta appears somewhat disrupted.”

Second loss: Miles (July 2007 at 18w 5d) cord stricture
Additional testing on me showed I am heterozygous for MTHFT mutation C677T

Lots of old blood in the amniotic fluid - not sure if there's any significance to this

I took baby aspirin during this pregnancy from 6 weeks onward

Anticardiolipin was normal this time

I do have two living children, a son born 2003 and a daughter in 2005. They also had placenta/cord issues, especially my son:

David (2003) - Lagging growth was first noticed at 20 week ultrasound and became more severe by 30 weeks

Born at term weighing 5 lb. 0 oz. with meconium and nuchal cord x1; APGAR 2/7; 5 days in NICU

We were told he had a small placenta and thin cord; this was not sent to the lab

Tania (2005) – Possible partial placental abruption during labor

We were told the placenta had “two sacs”; it was not sent to the lab

I don’t think there’s any way around my RE on this issue - I'm sure my Gyn wouldn't get involved and I’ve only met with a perinatologist once almost three years ago (she said use Lovenox but I don’t think she’d overrule my RE on when to start). The hell of it is, the doctor at The Other Clinic was going to have me on Lovenox from transfer! I don’t know if Lovenox/heparin two weeks earlier would make any difference, but I sure don’t want to end up holding another dead baby and wondering “what if”. *sigh* I’m feeling anxious, desperate, and disobedient, but there doesn’t seem to be any way to get my hot little hands on those syringes.

Lovenox / Heparin Question

After losing two babies in 2007, both at 5 months gestation, I was advised to use Lovenox in any subsequent pregnancy. I still haven't had the chance to try it, but I'm about to do IVF. The trouble is that my RE refuses to let me have Lovenox to start after retrieval, saying we'll see about it after (if) I have rising betas. Also, the dose would be low - a prophylactic dose of 40 mg/day rather than a therapeutic dose of 60-80 mg/day.

So I have a question for anyone out there who has used Lovenox/heparin in absence of definite proof of thrombophilia: When did you start and at what dose? And why exactly did you use it? With what outcome? I'm looking for personal experiences and also any references to studies/articles about any advantage to starting Lovenox before pregnancy is confirmed.

After my losses I was tested for everything under the sun. All results were negative except the following:

First Loss - Jeremiah (January 2007 at 21w 3d) cord hypercoiling
Moderate positive result on anticardiolipin antibody IgG, which we're told is not significant; after six weeks this was retested and the level was "inconclusive"

Normal chromosomes (except a pericentric inversion of chromosome 9 [inv(9)(p12q13)] inherited from mom - we're told this is insignificant

Second loss: Miles (July 2007 at 18w 5d) cord stricture
Additional testing on me showed I am heterozygous for MTHFT mutation C677T, which we're told is "not clinically significant"

I took baby aspirin from 6 weeks onward

Anticardiolipin was normal this time

I do have two living children, a son born 2003 and a daughter in 2005. They also had placenta/cord issues (esp. my son). I don't know if we're on the right track at all with the thrombophilia hypothesis. Maybe it's genetic? Something else? Any thoughts are appreciated.

Up until a few days ago, my time and energy went into fighting for the chance to even try IVF and then into arranging all the details (getting drugs, paying, etc.). Now the stress is really hitting me. I think my chances of getting pregnant are decent, but what about staying pregnant? I think with my terrible track record it's best to be aggressive with the Lovenox, but how can I when my RE refuses because the "cord isn't even formed that early". I wonder if my babies' cord problems are just a symptom of a larger implantation problem caused by thrombophilia. I'm terrified of having another dead baby.

Thrombophilia: Looking for clues in this and other cases

The frustrating problem with the two case studies I have is that there is so little evidence to either support or refute the thrombophilia hypothesis in these particular cases.

In the first case the woman lost 3 pregnancies in a row at 19, 16, and 15 weeks due to umbilical cord hypercoiling, stricture, and torsion. There is absolutely no information regarding thrombophilia testing or any other lab tests that were almost certainly performed after these losses. There's also no information on whether she tried any treatment such as heparin in any of the pregnancies. The report shows there was a 1.3 cm clot in the first placenta, but no clots found in the other two.

In the second case the woman lost 3 out of 4 pregnancies between 28 and 30 weeks all due to umbilical cord stricture. One of the 4 pregnancies resulted in a live birth at 25 weeks, presumably by C-section and presumably because of similar problems but it doesn't say. Also, like the first case there is no information on any lab test that were done or on whether any treatment such as heparin was tried in the later pregnancies. There is no mention of clotting in the placentas.

Thanks to Dr. Collins at the Pregnancy Institute in Louisiana, I was able to find out about a case where the woman lost 4 out of 9 pregnancies due to umbilical cord torsion at 19-20 weeks. Four of her pregnancies resulted in live births and the other was an early miscarriage. This amazing woman was kind enough to talk to me on the phone for an hour and a half telling me about her experiences. After having 2 normal pregnancies, she lost 2 babies at 19-20 weeks due to cord torsion. Then on the next pregnancy she tried using heparin (without strong evidence of clotting or thrombophilia on the first two losses). This pregnancy was also a loss. So after 3 late losses in a row, she tried again using heparin and got a live baby. The next pregnancy was another late loss despite using heparin, but the last pregnancy (also using heparin) resulted in another live birth.

This gives me hope that having a live baby is still possible even after repeated cord-related losses. However, it doesn't give much hope that heparin is the answer, since she experienced a loss rate of 50% (2 out of 4 pregnancies) without heparin, and a 50% loss rate (2 out of 4 pregnancies) with heparin.

In my own case, of course, I have more complete information on lab results, family and personal medical history, etc. as follows:

• No solid evidence of thrombophilia from any of the many lab test that were done. More specific results on a couple of tests listed below.
  

All labs on mom normal, except moderate positive result on anticardiolipin antibody IgG, which we're told is not significant; after six weeks this was retested and the level was "inconclusive"

Additional testing on me showed I am heterozygous for MTHFT mutation C677T, which we're told is "not clinically significant

• No family history of thrombophilia or clot related problems (heart attack, stroke, deep vein thrombosis, pulmonary embolism)
• No personal history of clots, despite 2 full term pregnancies and two "half" pregnancies (pregnancy, especially the postpartum period, is associated with higher risk of clots), 2 surgeries (also causes a higher risk of clots), and several trans-oceanic flights (also associated with higher clotting risk). About a week after laparoscopic surgery last year, I had the opposite of excessive clotting and instead bled too much, resulting in this lovely hematoma.
• The pathology report from my first loss does mention that fragments of blood clot were recieved with the placenta and cord, however I think this clot was probably formed at the time of delivery because the placenta did not come out in one piece. No mention of any clots found in either of the placentas in my case.
• Although all lab tests for thrombophilia came back negative, I still wonder if my circulation is not what it should be, whether because of some clotting issue or something else. I do have some symptoms associated with clotting disorders, including fetal loss (obviously), IUGR (my son was 5 lb. 0 oz. at term), and a possible partial placental abruption during labor with my second child, but no actual evidence of clots.
  

I have no idea what any of this means. Anything? Nothing? I think the case for thrombophilia as the cause of umbilical cord pathology is weak at best, however I would not bet my child's life on it. If I have the chance at another pregnancy I would try the daily heparin shots - gladly.