When Formalin is Not Your Friend (aka: Biopsy #3)

In general, I like my OB. Far more important than liking her, I think she's competent and will work with me on my care. Yesterday was not, however, one of our finer days together.

I went in for what I hope will be my last biopsy. She asked if I wanted to get three samples again: one for histology, one to culture for bacteria, and one to culture for yeast. Only the histology was positive last time, so it was reasonable to ask if I wanted to go through the unpleasantness of three samples. On one hand, I really hoped there was no need, and had no expectation of a need for bacteria or yeast cultures. On the other hand, if the histology comes back positive, I don't want to have to wait for another cycle to get another biopsy for bacterial culture. So we agreed to get three samples again.

She got three samples. I got up and got dressed. Just as I was about to walk out, she came back in and told me she'd put all three in formalin by accident, and you can't culture a sample that's been in formalin. If I wanted bacteria and yeast cultures, I'd have to do another biopsy.

Bloody hell.

Since we'd already run a catheter into my uterus once for the initial biopsy, it increased the chances of pushing in new bacteria and getting a false positive. Also, those biopsies are no bloody fun. I didn't want another. So I declined.

Let's hope the histology comes back negative for CE.

Other interesting notes:
October 30, 2016 was the day my water broke with the twins. During the biopsy, I mentioned to my OB that it happened a year ago. She commented that it must have been scary for me, and that she was scared, specifically that she was scared during my delivery a week later. I knew things were bad during delivery, but hearing that they were bad enough for my OB to be scared. . . I guess that's why my Dad, who saw them wheel me out to surgery that day, encouraged me to think about my own health before continuing to try to get pregnant.

I've had bleeding since the biopsy. More bleeding than my last period. I'm trying to tell myself that it's a good sign that my lining isn't shot. I have no idea if that's true or not, but it's giving me hope so I'll hold to it!

I told my OB that if I'm able to get pregnant again, I'll be coming to see her pretty early on, since I'll want the NIPT referral as early as possible due to the TAC. She told me she's happy to see me weekly if I'm pregnant again. She may regret saying that! :)

Who Moved My Zen?

Emotions are a roller coaster.

DH and I relocated to Minnesota four years ago. We love it here, but it's hard to make friends. Heck, it's always hard to make friends as an adult, but here in Minnesota, it's so hard there are even books on the topic of "Minnesota nice" - this concept that Minnesotans are super polite, but already have well established social networks and have no interest in making new friends. I've found that painfully true.

DH and I are both into bicycling. I've missed the last few seasons for medical reasons, but DH has kept up. I was really excited when he suggested we get together with a cycling buddy of his and the buddy's wife. Dinner was suggested and I was asked for a restaurant recommendation. There's a place DH and I enjoy, called Red Cow, so I suggested that. Turns out the other couple really like that place, too. Total win, dinner planned for yesterday.

Minutes before we're to walk out the door, I realize something. Exactly a year before, I was 16w6d pregnant with the twins and my mom was here visiting. We went out to Red Cow with her that afternoon. I got sick that night, something that seemed like mild food poisoning. The next morning my water broke around 7 am. 

Why the hell did I have to pick Red Cow? Why didn't I remember what day it was until that moment? Why couldn't I have forgotten that detail? Zen: shattered. Roller coaster: on the downswing. 

Past and Future

Today marks two weeks until surgery. Only a few days until my next biopsy. If all goes well, it's less than 30 days until I'm cycling again. I am suspicious that getting pregnant again is going to be somewhere between 'a lot more difficult' and 'impossible'. Why? Because even though I took estrogen this cycle, my period was 2 days of what could barely be classified as more than spotting. I'm worried my lining is totally and irrecoverably shot.

I am oddly zen about it all. Yes, the surgery is unnecessary if my lining 'can't get it up' as it were. But since we won't know about my lining until we cycle, and I absolutely will not cycle without the surgery, well, it all falls into the category of 'it will be what it will be.'

Tuesday was three months since we lost Quinn. The twins' first birthday is coming up. I don't feel right calling it a birthday, but there isn't another term I like better. Others just feel too cutesy (angelversary) or too harsh (stillbirthday). Let's just say that it's almost a year since we met and lost them. In some ways, it seems like it was yesterday. In other ways I can tell that I'm doing better than I was, even a month ago. I am having fewer bad days. The seasonal triggers produce moments or hours of memories and pain, not days. While medical stuff is on my mind a lot, when I think about my babies it's with love and longing, not the overwhelming grief I've felt recently. The only thing that makes me not zen is remembering that Quinn should have been born, at term, a month from now. Remembering that breaks my heart in a completely un-zen-like fashion.

At this moment, with the future still unknown, I'm ready to move forward even if moving forward doesn't bring us another pregnancy. I think that's the zen talking. I hope I can hang on to this zen in the coming months.

Fetal Membranes and Alpha Lipoic Acid, Continued

Before I end my treatise on fetal membranes, I thought it would be helpful to share an image of the layers of the fetal membrane. This is from a journal article, Extracellular Matrix Dynamics and Fetal Membrane Rupture (2013), Strauss, J. F.

Here's a quote from the article that I found telling: "It has been hypothesized that fetal membrane rupture involves a sequence of events that starts with distension and loss of elasticity, separation of the chorion and amnion, disruption of the chorion, distension and herniation of the amnion, and finally amnion rupture. This proposed sequence of events appears to be the result of structural alterations in ECM with resulting biomechanical changes in the membranes, primarily the amnion, which is the strongest component of the fetal membranes. Since cervical insufficiency is often associated with PPROM, it is likely that preterm cervical changes facilitate the unscheduled rupture of membranes in PPROM."

There are other articles out there that talk through specific dynamics of what happens to the various layers, if you're interested.

Finally, let's talk alpha lipoic acid (ALA) again.

I realized it might be useful to list the dosage that I've found in the research for alpha lipoic acid as it relates to prevention of pprom. The best study I've found so far is actually focused on prevention of PTL, and it found a massive reduction in risk from a daily dosage of the following: magnesium 225 mg, alpha lipoic acid 100 mg and vitamin B6 1.3 mg - 1x/day. Now, let me say that the reduction is so massive that I am really suspicious of the article. Either they're not correctly describing the population of study participants, or this is too good to be true. But it's probably worth a read if you're interested in research on this topic. Study: Efficacy of Magnesium and Alpha Lipoic Acid Supplementation in Reducing Premature Uterine Contractions (2014), Parente, et. al. I'll probably do a lot more reading on this topic and post anything I discover in the future.

The majority of studies I've found looking at alpha lipoic dosage in humans related to patients with diabetes. In that case, I am routinely reading dosages of 600 mg/day.

I also found a study that made my heart go pitty-patter: pregnant women with subchorionic hemorrhage. Those given both alpha-lipoic acid (300 mg 2x/day) resbsorbed the SCH more quickly than those on progesterone alone. See: Alpha Lipoic Acid (ALA) effects on subchorionic hematoma: preliminary clinical results.

I also found a single study looking at ALA with IVF patients. It found a higher number of grade 1 embryos in patients taking ALA plus myo-inositol . See: Effect of myo-inositol and alpha-lipoic acid on oocyte quality in polycystic ovary syndrome non-obese women undergoing in vitro fertilization: a pilot study. While that study is interesting, the population is small and using the patients as their own controls is really problematic - so take the results with an entire shaker of salt.

Beyond that, there are many studies using rats and suggesting that ALA protects against reactive oxygen species (ROS) which are correlated to damage to DNA and RNA and are considered agents of cell death. All sounds good, right? Sure, but be aware that ALA is also associated with effects on fetal hormones (protective effects, but effects none the less). In other words, do your own research and think very carefully before you consider taking it.

Infectious Diseases Specialist Visit

With the crappy news of another operative hysteroscopy, I got distracted and never posted about our appointment with the Infectious Disease Specialist at the U. Overall, it was a good experience. The TL;DR version: the initial CE finding was probably due to retained POC. It's probably unnecessary, but I can do 14 days of doxy and repeat the biopsy.

Here's the long version: The doctor (who was very pregnant herself) was extremely thorough. She spent well over an hour with us and walking through my complete medical history, going back to childhood. She even sent a follow up note to me asking if I'd had blood clots in the past, because she'd spoken to a colleague who is a rheumatologist, to see if my history of juvenile arthritis (JRA) might be playing a role.

The downside of such a long conversation and discussing so much history is that the conversation was a bit meandering. It's hard to tell the red herrings (JRA, recurrent sinus infections, 12+ years of incurable infection in two of my toes) from the relevant (chronic endometritis, recurrent UTIs). She mentioned something that I thought was really interesting, if frightening: in a proportion of women with recurrent UTIs, there seems to be a chicken and egg issue, where the surface of the bladder is inflamed, and that inflammation makes it more prone to bacterial growth/infection. No one is sure which comes first: the inflammation, or the infection. It can be really hard to break the cycle. This could be what's happening with my uterus, but there's no clear treatment approach if so.

She thought the CE from the biopsy might simply be because of the amount of debris that was in my uterus - retained placenta. She wanted, partly for research, partly for me, to have me do another biopsy before starting antibiotics. Our initial discussion was that we would do the biopsy, and if the CE is gone, I wouldn't do any antibiotics. However, I realized that with the FemVue, I would have to take a few days of antibiotics. Once we discussed that, the doctor agreed that if we were going to be on 4 days of doxy, we might as well do the 14 days of doxy that would be the normal first line treatment for CE. So, the plan was: biopsy and Femvue on 10/4. 14 days of doxy starting on 10/14. Repeat biopsy when my next cycle starts.

Of course, we didn't account for the repeat hysteroscopy in the plan, but it doesn't really change anything. I finished my doxy yesterday morning, and I'm now booked for what I really hope will be my last biopsy on the 30th. The pathology from this last hysteroscopy came back with no evidence of CE (YIPPEE!), and also no retained placenta. It appeared there was just a bit of scar tissue.

Preventing Fetal Membrane Rupture

Given my history, I'm quite interested in pPROM, and what might be done to reduce the risk of pPROM. The obvious answer is to prevent bacteria from ascending into the uterus, which we're hoping to accomplish via the TAC and clearing out my chronic endometritis. Beyond that, though, I wanted to learn more about fetal membranes.

Below are a selection of research articles I found. I've mostly included those that found consistent results. This is why you won't see any studies on Vitamin C below, as C has mixed results with respect to FM rupture. The caveat: read these and make your own decision, and note that the researchers are often the same across these studies. I will say that if I"m ever pregnant again, I intend to stay on progesterone (P4) and take Alpha-lipoic acid.

Fetal Membrane structure (FMs):
Fetal membranes are composed of two layers, the chorion and the amnion. During pregnancy, a weak zone in the fetal membranes typically develops over the cervix. This is the spot that typically ruptures during a normal labor.

In various modeling and testing, the amnion is the most important component of FM with respect to strength. Thinner amnion and chorion are correlated to lower strength and greater risk of rupture.

See: Function and Failure of the Fetal Membranes, (2017) Verbruggen, et. al.

Etiology of FM rupture:
When looking at the weak zone that appears over the cervix in a healthy term pregnancy, researchers find remodeling of the collagen that makes up the FM. Inflammation/infection and bleeding/abruption both produce the same collagen remodeling effect, when modeled using TNF (for infection) and Thrombin (for abruption).

See: The physiology of fetal membrane weakening and rupture: Insights gained from the determination of physical properties revisited. (2016) Kumar, et. al.

Correlates with FM strength:

"The dietary supplement α-lipoic acid and progestogens (P4, MPA and 17α-hydroxyprogesterone) have been shown to inhibit both TNF and Thrombin induced FM weakening. The progestogens act at multiple points by inhibiting both GM-CSF production and GM-CSF action."

See: The physiology of fetal membrane weakening and rupture: Insights gained from the determination of physical properties revisited. (2016) Kumar, et. al.

Alpha-lipoic acid moderates the impact of both TNF and thrombin on FM. "Treatment of FM with 0.25 mM LA completely inhibited thrombin-induced FM weakening and MMP expression (all p < 0.001). Thrombin treatment of cultured FM induces mechanical weakening and increased MMP3 and 9. Treatment of FM with LA inhibits these thrombin-induced effects. We speculate LA may prove clinically useful in prevention of PPROM associated with abruption."

See: Alpha-lipoic acid inhibits thrombin-induced fetal membrane weakening in vitro. (2010), Moore, et. al.

"TNF and thrombin both weakened fetal membranes and elevated media GM-CSF levels on the choriodecidua side of the fetal membrane. Pretreatment with progesterone, MPA (medroxyprogesterone acetate), or HP (17α-hydroxyprogesterone) inhibited both TNF- and thrombin-induced fetal membrane weakening and also inhibited the induced increase in GM-CSF. GM-CSF decreased fetal membrane rupture strength by 68%, which was inhibited by progestogen pretreatment with a potency order: progesterone <MPA <HP"

See: Progesterone inhibits in vitro fetal membrane weakening. (2015). Kumar, et. al. 

Nothing Much

There's nothing much going on here, which I hope is a good thing.

A quick glance in my pill bottle tells me I have 4 doxycycline left! I have no side effects or symptoms, so I'll just hope they've done their job.

Last Friday I received the order for the repeat Infectious Diseases screens for DH and I. I still think this testing is utter bullshit, since we're using TI and have been through multiple screens in the last 16 months. We pose no infection risk to anyone at the office (and shouldn't even if we were carriers, given the need to follow UP). Alas, sometimes you have to wade through bullshit to get what you want, so in I go.

It's looking like I'll get my screen and my repeat biopsy done around 10/31, which should be CD6. Of course, by having written that, I'm sure my cycle won't start as expected! I have 25 days left until surgery. I'm trying to make the most of the time - back to daily workouts and a fairly clean diet. Once my next period starts, I'll go hardcore on the clean eating. I doubt it makes a difference, but I also don't think it hurts, and I continue to want the comfort of feeling like I've done everything within my control in this utterly uncontrollable situation.

If everything goes well with surgery, I'll have to make a decision about when to start cycling. Dr. Haney told us he wanted us to have one period before going back to the RE. If my cycles stay roughly the same as they have been, that should mean CD1 falls about 10 days after surgery. If I do well, it shouldn't be a problem to start stims then. Given my age and insurance coverage, I'd much rather cycle in November, but I'm not sure what will give us the best chance or be the best for my body. I guess we'll wait and see.

Lessons from Surgery

I realized last night that having had seven surgeries in less than two years, I might have some advice that's helpful to anyone else preparing to go through gynecological surgery. Thus, here are my "credentials" and also my experiences/advice.

Surgeries since 1/18/16:

1. D&C for missed miscarriage - Jan 16
2. Operative hysteroscopy to remove scar tissue and retained POC from missed miscarriage - May 16
3. Emergency D&C due to postpartum hemorrhage - Nov 16. To be fair, they did two of these, since I Started to hemorrhage again while in recovery before regaining consciousness.
4. Operative hysteroscopy to remove scar tissue and retained POC from losing the twins - Feb 17
5. Rescue cerclage placement - July 17
6. Operative hysteroscopy to remove scar tissue and retained POC from losing Quinn - Sept 17
7. Operative hysteroscopy to remove scar tissue and retained POC from losing Quinn - Oct 17

Things I have learned throughout this process. These may only apply to me, but I thought it was worth sharing:

• If you can, get a morning surgery. Going without food until an afternoon time slot makes an unpleasant day worse.
• Be aware that even though you're groggy, you'll have awful insomnia starting around midnight the night of/after the anesthesia (this applies only to the general anesthesia and not the spinal)
• Be aware that you'll stay groggy the day AFTER surgery.
• Know that it's ok to ask to have the IV placed in your arm, not your hand - often that hurts less. Either way, plan on about a week of bruising from it.
• Expect 2-3 days of sore throat from the anesthesia. How sore will depend on how long you were under. 
• If you're allowed, plan on a shower as soon as you get home - different hospitals do a better or worse job of cleaning up the betadine they use on you, expect that you'll still be orange in a few places until you can shower. 
• If you're outpatient, be aware that the doctor will tell the person you came with the outcome of the surgery. This means that if you have specific questions you want answered, make sure to tell that person. I expect my DH to know what's going on and ask the right questions, but in reality, all he's able to process without specific guidance is, "It went well."
• Wear comfy clothes and a bra that are easy to get back on. At the hospital, a nurse dressed me while I was in post-op. At the surgical center, I had to dress myself in the tiny pre-op/recovery room. In either situation, you want easy to doff/don clothing. 
• If you get cold easily, bring a jacket you can throw over your shoulders while waiting. Yes, hospitals and surgical centers have warm blankets, but they're often about 2" by 2", so it's tough to really bundle up! My local hospital offers a warming gown, but the surgical center doesn't, so having a jacket over my shoulders while waiting to be taken back for surgery was awesome.
• Have a pain management discussion with your doctor before you go under. My first two surgeries, I was given narcotic painkillers and rx strength ibuprofen. I never needed the narcotics, I did appreciate the rx strength ibuprofen. Surgeries 4, 6 and 7 we never discussed pain management, and since I can't take NSAIDs, I went without once home. That's ok by me, but if it's not ok with you, be sure to discuss with your Dr.  
• Have a plan for what to do when you get home. My plan is Netflix under a blanket on the sofa, but figure out what low-energy thing will be a treat for you, and have it ready.  

Most of all, my advice is that you CAN get through this, no matter how scary it seems. 

Still Not 1/18

I spent quite some time trying to come up with an appropriate title for this post. A few I tried on:
You've Got To Be Kidding Me
Really, Uterus?
Again!?!
Motherf*cker!!

That last one still feels the most appropriate.

Today was the repeat endometrial biopsy and FemVue. The FemVue's goal was to check my tubes and make sure nothing was left in my uterus. Tubes looked great. Uterus? Not so much. Don't know if it's placenta or adhesions, but up near the fundus something remains. It was obvious enough I could pick it out on ultrasound, and I suck at reading u/s.

I'm not surprised - my period has been unusual, and there was fluid in my uterus before they started the FemVue, which didn't bode well. Alas, this means another operative hysteroscopy. If it means another week with a stent . . . if it means another week with a stent I'm thinking very hard about canceling the surgery and giving up. Because a uterine catheter is hell. Just hell. No better description. Surgery is booked for Friday, and if I think too long about it, I'll back out because I'm just not up for that hell again.

So I won't think about it, I'll just do it.

Oh, and for the record, today's biopsy hurt a lot more than last month's. The FemVue didn't hurt at all during, but I still have odd abdominal tenderness afterward. Fun times.