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! :)

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. 

One Surprising Step Ahead

Today was my MFM consult. Some of it went as I’d have expected, other things were very different. Starting off, the first and biggest recommendation the perinatologist had was to get a pre-pregnancy transabdominal cerclage. With Dr. Haney. I wasn’t expecting that at all, but it turns out she had a patient with an identical history to mine. Lost twins due to pprom. Lost a singleton to IC. Did a TVC and kept culturing and treating the bacteria they found during pregnancy. . . . and still lost that pregnancy. So they sent her for a TAC, and she recently delivered a 39 week baby.

To say that recommendation was a pleasant shock is an understatement. While I was hospitalized and talking to another MFM in the group, he told me we’d place a TVC at 12 weeks during future pregnancies. I had pushed back, hard, on why you’d do a TVC, especially in someone with infection issues, and not TAC. He was adamant about the TVC being the right choice. So to hear the number one recommendation being a TAC, and to be told to go to Haney, that made me feel much, much better about my decision. It also means I'm one step ahead of the game, having already consulted with him and booked surgery.

On the subject of infection, this perinatologist, Dr. N, agreed with Dr. Haney that the underlying cause of both losses was cervical issues. Even though my cervix was long and closed after Zoe’s water broke. Even though Zoe was the higher baby, and bacteria should rupture the lower baby’s membranes first. She truly believes that there’s no scientific benefit or merit in looking for chronic endometritis, and that treating any bacteria found in my uterus that don’t belong there would cause other problems, as she saw in the patient previously mentioned. Having said all that, we pressed really hard and she agreed to request an endometrial biopsy and a consult with the true Infectious Diseases department. So, on 9/6, I go in for my SIS and a biopsy. Based on what those show, we’ll figure out what comes next.

Dr. N mentioned that infectious diseases would probably screen me for various autoimmune issues that interact with infections. With my history, that seemed wise.

On the topic of progesterone, she noted that it’s shown to help in cases of cervical shortening before 24 weeks, but with the TAC I will not have cervical shortening. Thus, she can not see any clinical benefit. At the same time, she’s willing to discuss further/prescribe it, if I get there, because there’s no harm either. The same goes for additional cervical monitoring during pregnancy. No need, but no harm, and there’s something to be said about the positive impact on my anxiety levels.

With respect to my Asherman’s, and my history of autoimmune disorders, that’s unlikely to be related to pPROM. I will have my placenta monitored more closely during future pregnancy to make sure there are no IUGR or placental insufficiency issues caused by the Asherman’s.

So, the plan:
1. During next cycle (which started when I walked out to the parking garage after the appointment) get endometrial biopsy and confirm uterine cavity is clear of scarring. At the moment I’m scheduled for a biopsy and SIS, but that may be replaced by a biopsy and hysteroscopy.
2. Consult with Infectious Diseases. Determine treatment based on biopsy and results.
3. Have TAC placed.
4. Return to CCRM for COH.

DH and I need to talk a bit more, but it’s a plan I feel pretty good about. It may not get us a THB, but I will feel confident that we’ve tried EVERYTHING we could in getting there.

Blocking the Exit

Earlier this month, we had a telephone meeting with a doctor who could probably be described as the expert in transabdominal cerclage. His name is Dr. Haney. Due to my cervical issues this pregnancy, we’re unwilling to consider trying again without a better option than a(nother) transvaginal cerclage. Dr. Haney, who is located in Chicago, appeared to be that better option. For the sake of my record keeping, I’m going to use this post as a place to track what we learned during our two hours on the phone with him.

The Consult

Here’s my best translation of what Dr. Haney told us. I’m not agreeing/disagreeing with anything, just trying to reproduce in my own words what I heard from him. Since this was filtered through my memory/lens, take it for what it’s worth!

The cervix is like a tube or a spindle: there’s tissue around an open canal. Of that tube, 2/3rds of it is up in the abdominal cavity, attached to the uterus, and the last third is down in the vagina. There is a band of tissue at the top of the cervix, the part in the abdomen, that remains tightly closed. During labor, the pressure of the baby’s head, plus contractions, is what forces that band to dilate. But outside of labor, it stays tight. That’s in a woman without cervical insufficiency (CI).

In a woman with CI, the entire column of the cervix dilates from the internal opening downward as the relatively small pressure from the growing baby presses down due to gravity’s impact. As the cervix dilates, bacteria can get into the uterus, and the membranes of the amniotic sac can tear free from the uterus and prolapse out into the cervical canal and vagina.

With a transvaginal cerclage (TVC), a stitch is placed in the lower third of the cervix. Women who have true CI and a TVC will funnel down to the stitch, because nothing has been done to prevent the upper 2/3rds of the cervix from dilating. This means membranes will pull away from the wall of the uterus, and bacteria from the vagina will be able to ascend to the uterus. If I understood Dr. Haney correctly, his position is that women with CI and a TVC will always wind up with chorioamnioitis because of this ascending bacteria. The chorio in turn worsens the chances of survival for their infants. Having had chorio with all three girls, and knowing that Alexis and Zoe passed before birth due to severe chorio, this was a painful reminder of everything that we’ve been through.

With a transabdominal cerclage (TAC), a 2-3 inch incision is opened at the bikini line. A woven fiber band is tied around the cervix at some point in the upper 2/3rds. In my case, Dr. Haney would place two bands. Each band has the strength to support 100-120 pounds, so they could easily support the weight of a fetus, placenta, amniotic fluid, etc. With the bands in place, dilation is impossible. They’re not tied so tight that the cervix is occluded, but they are tied tight enough that the membranes can’t ever prolapse and the cervix can’t funnel. The result of this is that the mucus plug stays in place, the cervix stays long (~4cm) and bacteria can’t ascend from the vagina. The other results: while one can have periods, first trimester miscarriages, and get pregnant “the old fashioned way,” one will have to have a c-section for any 2nd trimester delivery. There is also a risk of uterine rupture as the cervix can’t dilate if contractions occur, and something’s got to give.

Dr. Haney reported a 99% success rate, where success is defined as a live birth, and even mentioned that 92 of 92 sets of twins whose mothers he performed TACs on were born live. He noted that when babies are born before term with TAC in place, it’s due to other issues.

What are my feelings on all of this? 

I agree with the belief that TAC has much higher success rates than TVC, when you define success as live birth. There are numerous studies, most from outside the US, to support this. If we try again, I will have a pre-pregnancy TAC placed with Dr. Haney.  There is no question in my mind about that. Having said that, the “other issues” that cause pre-term deliveries are also very relevant to me, and I’m concerned they were minimized during our conversation. That’s probably because I was talking to someone who specializes in TACs and not the other issues, but I know exactly how this works: any complications I have during pregnancy post TAC my local MFM team will blame on the TAC. The TAC expert will simultaneously assure me it’s not due to the TAC and that I should work with my MFM team.  The end result will be suboptimal because everyone will be busy pointing fingers at everyone else. Cynical much? Why yes, I am.

Next steps

From my point of view, there are two issues that must be addressed before we decide to try for another pregnancy. First, infection. There’s a growing body of literature correlating first trimester miscarriages and failure of genetically normal embryos to “take” after IVF transfer with asymptomatic, chronic endometrial infection. Correlation isn’t causation, and there are plenty of women with term deliveries who also show these markers of infection (related note, I found a study showing a decent percentage of healthy pregnancies in the 36-38 week range have chorio, but no one ever looks for it because there’s no reason to).

Looking at my personal history, I had more than 15 years of recurrent UTIs. They started when I was a kid, a few times a year, and by early 2010, I got them every month or two. I would take my antibiotics each time, the symptoms would vanish, until the next trigger caused the infection to flare up again. In 2010 I was finally referred to urology. The urologist confirmed that there were no structural abnormalities, and then told me that in some people, the bacteria just hang around. The antibiotics knock them back enough to reduce symptoms, but as soon as conditions are right again, they go out of control. I was placed on 6 months of low dose macrobid, and had my last UTI in 2010. At least, my last until 2017. Long way of saying that I have a history of bacteria hanging on through antibiotics that should have cleared them. And bacteria that were asymptomatic until something triggered their uprising. Now I can’t help wondering if ‘pregnancy’ is what’s triggered uterine bacteria.

So, we must clear up the infection issue before we can make a decision to try again.

My cervix is the second issue. I think the TAC with Dr. Haney will address that. It comes at a high risk and a high physical cost, but it’s as good of an option as exists. Honestly, I’m grateful that there IS an option that works so well to solve one of my issues, even if the associated risks are great.

Overall, more answers, one potential solution, more risk and fear.