Low estrogen and progesterone levels in the first trimester after a frozen embryo transfer

I generally did not have good luck with my frozen cycles.  We did 5 frozen cycles, and had 3 very early miscarriages and my last pregnancy, which miscarried at 12 weeks after we saw multiple fetal abnormalities.  Of course, I didn’t have amazing luck with my fresh cycles either.  My first one produced my wonderful son.  (Jackpot!)  My second one was a blighted ovum, and my third was the anencephaly pregnancy. 

Because my last pregnancy was the only frozen one to go beyond an early blood test, it was my first time being pregnant with the hormonal issues of a frozen cycle.

My estrogen and progesterone levels remained low throughout the pregnancy.  Because they were low, I ended up staying on both supplemental estrogen and progesterone into my 12^th week—ironically I went off both of them the day before we found out there was no heartbeat.  (Yes, I had needle-sized shots for over 12 weeks just to end them the day before we lost the pregnancy.  My butt STILL hurts.) 

The nurses poo-pooed my concerns about my low values, suggesting that it is normal to have lower values during a frozen cycle.  But my fertility doctor suggested that there could be an association with poorly rising values and birth defects/pregnancy loss.

So, no huge surprise after having pretty low levels we lost the pregnancy.  For the record, here are my values: 

Estrogen

Pre-transfer  – <12

4w2d – 265 [3 estrogen pills/day]

8w3d – 622 [3 estrogen pills/day]

9w6d – 1316 [3 estrogen pills/day]

10w6d – 866 [1 estrogen pill/day]

11w5d – 941 [1 estrogen pill/day]

12w5d – 991 [1 estrogen pill/day]

Progesterone

4w2d – 22.9 [1ml progesterone in oil shot/day]

8w3d – 27.3 [1ml progesterone in oil shot/day]

9w6d – 30 [1ml progesterone in oil shot/day]

10w6d – 32.6 [1ml progesterone in oil shot/day]

11w5d – 29.3 [1/3ml progesterone in oil shot/day]

12w5d – 22.8 [1/3ml progesterone in oil shot/day]

This article suggests that estradiol should be much higher than mine was, as it should be in the thousands by the second trimester:

http://perinatology.com/Reference/Reference%20Ranges/Estradiol.htm

And here’s a great one that suggests low estrogen levels during pregnancy can reduce the fertility for daughters:

http://umm.edu/news-and-events/news-releases/2001/low-estrogen-levels-during-pregnancy-can-reduce-future-fertility-for-female-offspring

Awesome.

PONTI Study: Maybe inositol is the magic bullet

The PONTI Study released its results right around the time we started our frozen cycle last time:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4825100/

As expected, they reported that (at least in their small study) neural tube defects were less likely to appear in the group that took folic acid and inositol.

Of course, the authors note that although NTD recurrence is generally thought to be low in the literature, their study found it to be higher, likely because their participants were taking folic acid in their original NTD affected pregnancies, and thus were likely to have folic acid resistant NTDs:

In contrast, the great majority of women who entered our study had experienced an NTD despite taking 0·4 mg FA in their earlier pregnancy. One could argue that this group of women may have been particularly enriched for FA non-responsiveness, and thus might not have been particularly protected by FA usage in their subsequent pregnancy. Several studies have reported NTD persisting despite voluntary FA supplementation in a FA-fortified population( 5 , 6 ), leading to the conclusion that a significant proportion of NTD may be FA non-responsive( 34 , 35 ). Therefore, although such women will continue to have 4–5 mg FA prescribed for their subsequent pregnancies, it seems likely that additional supplement protection, perhaps by inositol, will be needed to reduce their otherwise high NTD recurrence risk.

In other words, talking folic acid drastically reduces incidence of NTDs, but does not eliminate them because it appears some NTDs are “folic acid resistant.”  For women who were already taking folic acid and had a NTD pregnancy, they’re (we’re) probably in the folic acid resistant group.  That sucks because the incidence of reoccurrence is probably much greater in that group. 

Also note that the PONTI study was relying on people to get pregnant naturally.  You’re in a different bucket if you have a NTD pregnancy AND infertility.  (Infertile women and IVF patients are far more likely to have pregnancies complicated by birth defects.)  Yuck.  (Not yuck for me—I’m not getting pregnant again.  But yuck for anyone who has a NTD pregnancy after going through IVF.) 

I guess we just have to cross our fingers and hope that the PONTI study researchers are right and inositol can help the folic acid resistant group… and that it does not cause any other issues.

I should mention that I took inositol for all of my pregnancies after my anencephaly pregnancy.  None of those pregnancies were successful, and at least one suffered from severe birth defects, but I also did not have a repeat NTD pregnancy.  (In my last pregnancy, the baby’s head appeared round.  Her spine was developing abnormally, and was not formed enough to diagnose spina bifida.)

Folic Acid: Not Always A Magic Bullet

As we know from previous discussions, folic acid-supplementation does not prevent all neural tube defect pregnancies (see my next post on the PONTI study).  I was on 800mg of folic acid (double the recommended dosage) and I had a pregnancy with anencephaly, so at least that level of folic acid did not help me.

There is some suggestion that folic acid supplementation does not actually protect against NTDs, instead it just causes those pregnancies to end in miscarriage:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3677196/#!po=18.9655

“Contrary to expectations, in a few mouse NTD models FA treatment resulted in detrimental effects, including an increased risk for NTDs and embryo loss prior to the time of NTC (29, 30). Although it is largely assumed that FA prevents NTDs by correcting the embryological defect, these findings of early embryo loss are consistent with the possibility raised back in 1997 based on miscarriage risk that embryo loss may explain some of the decrease in human NTD occurrence upon FA supplementation (31). If these unexpected findings are relevant to human NTDs, it could suggest that, for certain mutations, FA may not be protective or even neutral in its action, although the consensus is that in humans, at a population-scale, FA has a preventive effect.”

This study suggests that for some mice (and thus maybe some people), folic acid supplementation may not be beneficial.  In other words, there’s a theory that if you take folic acid you’re NOT increasing your chance of having a healthy pregnancy.  You’re just decreasing the chance you’ll have a pregnancy with a neural tube defect because you’re making it more likely a neural tube defect pregnancy will end in miscarriage.  Interesting theory.

The same article questions whether there are some harmful effects of folic-acid fortification:

            

“Moreover, questions have been raised as to whether the increase in FA intake acting through the methylation cycle may predispose to allergic airway disease, although the current evidence is conflicting (33–35). With respect to NTD risk, some mutant mice showed a beneficial response to increased FA over a single gestation period but a detrimental response over multiple generations (30). This contradictory response depending on the length of FA exposure highlights the difficulties in considering how best to model human exposure to FA as currently implemented. Moreover, it raises the important but little studied question of whether there may be unexpected effects of long-term FA fortification and supplementation in humans or potential effects due to increased levels of metabolized and unmetabolized FA.”

So this article is considering exactly what I’ve worried about—what if folic acid (especially the large doses [5000mg] I was on after my anencephaly pregnancy) is actually harmful?  Folic acid allegedly promotes new cell growth.  What if that’s NOT desirable at some levels?

I found at least one article suggesting that high levels of folic acid in early stages of pregnancy might be harmful to the developing fetus:

http://www.hindawi.com/journals/jnme/2012/837901/

“Fetuses are exposed to high concentrations of folate during early stages of development because mothers are advised to consume folate supplements during pregnancy to lower the incidence of spina bifida [89–91]. As a result, the combination of folic acid with high concentrations of circulating estrogens during early stages of development may cause an additive or synergistic effect on DNA methylation [88]. These changes in DNA methylation patterns have the potential to induce both beneficial and adverse effects on the developing genome. Future research is required to confirm whether early exposure to environmental estrogens can alter the plasma estrogen profile enough to induce long-term programming effect on the developing fetus.”

I was always worried that I was taking so much folic acid I might actually be harming my developing babies, and I think I was right to worry.  Specifically, I worried if too much folic acid might cause birth defects.  Maybe.  Maybe.

For most “normal” people who are on normal amount of folic acid (400mg), there does not appear to be an increased risk of miscarriage:

http://ajcn.nutrition.org/content/81/5/1213S.full

http://www.webmd.com/baby/news/20010906/folic-acid-doesnt-increase-miscarriage-risk

D&C/D&E – third time in a year

My surgery was last Thursday, and I think it went well.  

I had a luminaria put in the day before the procedure (which, once again, really hurt going in), but it fell out that night.  I called the doctor’s after hours number and was told not to worry about it.

Since I’ve had TWO other surgical procedures in the past year, I knew what to expect.

The first time (my anencephaly D&E), I was sobbing more or less uncontrollably most of the time during the pre-op.  Unfortunately they did not let my husband back in the room with me, so I was crying all by myself.  It was awful.  For my second procedure (D&C to remove retained tissue after the first D&E), I was a woman on a mission because I did not want the retained tissue to slow down our next frozen cycle (which didn’t work anyway).  The pre-op was the same, but the surgery was really quick.  This time, the baby was measuring 12 weeks, but I was almost 14 weeks since my LMP, so my doctor said the procedure was a D&E (because she would be doing some cutting), but with the lower risks of a D&C.

I was far more calm this time (I did not cry once), but we learned our lesson the last two times.  My husband and I insisted he be permitted to come back to pre-op with me, and they let him.  I suspect that may have as much to do with which nurse is on duty, but it’s worth asking / demanding.  I wish he’d been with me the first time.

As for the procedure, I knew what was coming.  Get blood taken.  Sign some forms.  Talk about surgery with nurse.  Talk about surgery with doctor.  Meet with anesthesiologist.  Meet with nurse anesthetist.  Take antibiotics.  Get fitted with leg cuffs (that keep blood circulating while you’re out?) and those little conductor things on your body.  Get IV line.  Versed.  Get wheeled back to surgery.  Propofol.  Out for an hour during surgery.  In recovery.  Meet with doctor.  (Sometimes remember, sometimes don’t.)  Husband meets with doctor in waiting room.  Once lucid, husband can come back into recovery room.  Crackers.  Juice.  Home.

One pre-op difference was this time, when I met with the anesthesiologist, I asked about the drugs we were going to use.  The last two times they used Versed when I was still in the prep room and I was out by the time we got into the surgery room.  Then they used light Propofol in the surgery room to keep me out.  I was actually looking forward to the Versed—it was like getting lightly drunk and calm—but then he said he thought he could do the whole surgery just with Propofol.  I was clearly very disappointed, and asked repeatedly why this time was different.  He suggested if I wanted to do Versed first with light Propofol that would work too.  My husband was clearly very, very nervous that I was dictating how they were going to be drugging me.  Literally the only good thing about the entire process the last time was the Versed, and they were trying to take it away from me.  (Maybe it’s because I was not as hysterical this time, but the Versed did not seem to do anything.  They gave it to me right before we left, so I was still wide awake when we first went into the surgery room.  I remember them moving me to a new bed and getting things situated.  Then I was out.  I never got that peaceful calm, but maybe that’s because I was already pretty calm.)

The big post-op difference between this surgery and the last one was that I lost a lot of blood this time.  They expect patients to lose 100-200ccs of blood after a D&E.  I lost over 500ccs.  The doctor told my husband (when I was still loopy) that the heavy bleeding could be related to my abnormal placenta.  (Did he ask what was abnormal about it?  Noooo.)  From what I’ve read, it will take me about three months to replace all of the blood I lost.

I called the next day to ask—what was abnormal about my placenta?  She said there was something abnormal about the attachment of the placenta to the uterus, as it was actively bleeding during the surgery, which is rare.  When I suggested maybe it was because of the hematoma, she said she did not think so—hematomas are, apparently, not uncommon, and tend to produce just old clotty blood.  The active bleeding was unusual. 

(Here’s an article that describes >500cc as “hemorrhage” level bleeding.  It also gives some thoughts on causes of post-abortion bleeding:

http://www.societyfp.org/_documents/resources/guidelines2013-1.pdf)

I bled a lot the day of the surgery (changing a large pad every 2 hours), but it slowed down the day after.  For the first 24hrs I just laid in bed.  Once it seemed like the bleeding had slowed, I started moving, and I have not had much bleeding since the second or third day.  So that’s good.  (I think I bled for a while after my first D&E.)

I have not had any pain at all.  (I was uncomfortable after my first D&E, but I don’t recall taking any strong pain meds.)  They sent me back with a few really good narcotics, just in case.  Guess I’ll have to save those for a rainy day.  Haha, just kidding.

Emotionally I’m in a MUCH better place than I was after my first D&E.  (I knew the chances of this pregnancy continuing were small, and I was just removing an already passed away pregnancy.)  Physically I’m also doing much better.  I gained much more weight last time, and I started at a higher weight.  This time I started at an adult all-time low weight, and “only” gained 9 lbs.  (You’re not supposed to gain that much weight in the first trimester, but I was on total physical restriction for a large portion, felt awful, and stress ate.)  I also have a much better idea of what I have to do to recover—physically and emotionally—and have already started working on it.

So I guess what I’m saying is, I’ll be okay.

Recurrent miscarriage / IVF linked to birth defects

I’ve been pregnant ten times (depending on how you count).  One ectopic pregnancy that required two shots of methotrexate to terminate.  A second ectopic pregnancy (resolved naturally but further scarred my fallopian tube).  A very early undiagnosed miscarriage.  After those three we turned to IVF.  My IVF baby boy.  A blighted ovum.  A very early miscarriage.  My anencephaly pregnancy, terminated at 17 weeks.  Two very, very early miscarriages.  My omphalocele miscarriage, D&C at 13 weeks. 

That’s not a great record.  And, unfortunately, the fact that I had so much trouble getting pregnant and that I had so many miscarriages was probably just an indicator I was fucked.  So no surprise that I had two pregnancies marred by very rare birth defects.  

Recurrent pregnancy loss is an indicator for increased risk of birth defects:

http://www.ncbi.nlm.nih.gov/pubmed/8290380

IVF just makes it worse.  Women who have IVF are more likely to have pregnancies with birth defects.  Most of that is probably because of the population of women doing IVF (old, infertile), but the process itself probably plays some (small, hopefully) part.  

This article suggests that there is an increase in birth defects when IVF is used, but it’s almost entirely (but not exclusively?) explained by “maternal factors” (i.e. age):

http://humrep.oxfordjournals.org/content/16/3/504.full

For some things (including neural tube defects and omphalocele), there was a three-fold increase in incidence when fertility treatments are used.

This article suggests that there is an increase in birth defects when ICSI is used with IVF:

http://healthland.time.com/2012/10/22/ivf-linked-to-more-birth-defects/

Fetuses with Beckwith-Wiedemann syndrome (what we were worried about) were more likely to have been from assisted reproduction than were babies with isolated ompaloceles:

http://www.ncbi.nlm.nih.gov/m/pubmed/19107956/?i=2&from=/19367563/related

What does one do with this information?  Well, of course, you hope that if you do IVF you are one of the vast majority of people who do not have any issues.  I suspect my issues had less to do with the process of IVF (although it couldn’t have helped) and more to do with genetic issues that made me infertile in the first place.

Melancholia / The End

After we got our bad news at 11w5d, I mourned and then sprung into action.  I read all about omphaloceles and the syndromes associated with them.  I researched surgical options and looked at which hospitals and surgeons had experience.  I was going to everything in my power to protect that little one.

When people who knew what was going on asked me how I was doing, I was honest—for the first time since I got pregnant I was actually happy-ish.  I chocked it up to the fact that I had been so certain something terrible was going to happen that when it actually did, I was ready for it.  (If you’ve seen the movie Melancholia, the premise is that Kirstin Dunst’s character is suffering from severe depression, but is better able to handle really bad news—I won’t ruin the ending—than others around her.  The director, Lars Von Trier, has acknowledged that he suffered from depression, and the movie is based on his insight that depressed people have a tendency to remain peaceful during catastrophic events.  I thought maybe something like that was going on with me.)

So, on the day of our 12w6d follow-up appointment, I was ready.  We were meeting with a doctor with a background in genetic issues, we were meeting with the geneticist, and we were also going to meet with a fetal cardiologist (?!)  I had a list of questions a page long.

Our appointment ended up being pretty quick.  The sonographer started and I saw it right away—no heartbeat.  I said, “there’s no heartbeat.”  It was the first appointment when I expected a heartbeat, but it wasn’t there.  She started stuttering and jumped out of the chair saying she had to get the doctor.  (I did not hear her acknowledge there was no heartbeat, but my husband said she did.)  The doctor confirmed it—baby’s heartbeat stopped sometime last week, probably just a day or two after our last appointment.  The doctor asked if I noticed the cessation of pregnancy symptoms and I said no.  But I reflected later—I finally started to feel happy / hopeful right around the time she passed away.  I wonder if that was that mother’s intuition that I’ve been talking so much about.  I was so, so sad/scared for so long, and then when she was gone I felt at peace. 

Because of her position, we did not get any further information.  And we did not end up doing the CVS either.  Instead, I am going to have a D&C and we are going to send a tissue sample out and see if we get any further information.  (Was it a chromosomal issue, a syndrome, a diagnosable genetic issue?)  I’m not sure what we’re going to do with that information, though.  There’s nothing that can be done to help this pregnancy, and we’re done.

We still have 2 embryos left, but we’re not planning to try again.  This has taken every last bit of what I have out of me, and then some more.  I know I said “no embryos left behind,” but that was before we had two pregnancies that had severe and rare genetic issues…. and 7 other pregnancy failures.  I can’t put myself through any more cycles, and I have no confidence that if we even tried again it would work.  I’m going to move forward with my life and celebrate the one healthy little guy I do have.  

I did a bit more research, so I will make a few more posts in the next few weeks just to put what I have out there in case it can be helpful to anyone else.

I’d like to thank all of my online friends for their support.  As I lamented throughout this process, there were lots of times that things felt too heavy to discuss with my friends/family, who really don’t understand anyway.  It was nice to have little nudges of support.  It really meant a lot to me, especially during some very dark times.  (Special thanks to Emily, DublinerinDeutschland, Lauree and Mike, Melissa, and Unknown.)  I wish all of you the very best.