“Midtrimester amniotic fluid matrix metalloproteinase-8 (MMP-8) levels above the 90th percentile are a marker for subsequent preterm premature rupture of membranes.”

Abstract: Objective: We sought to determine whether midtrimester amniotic fluid levels of matrix metalloproteinase-8 were associated with subsequent preterm premature rupture of membranes.Study design: We conducted a case-control study examining 57 asymptomatic women who underwent genetic amniocentesis from 14 to 21 weeks’ gestation and subsequently had preterm premature rupture of membranes (<35 wk) and 58 women with subsequent term delivery. Measurement of total matrix metalloproteinase-8 level in amniotic fluid was conducted using a commercially available enzyme-linked immunosorbent assay and association with preterm birth due to preterm premature rupture of membranes was assessed. Results: The overall distribution of matrix metalloproteinase-8 concentrations was similar in women who had preterm premature rupture of membranes and term controls (median 2.39 ng/mL, 25th to 75th percentile 1.1-10.1 vs 2.37 ng/mL, 25th to 75th percentile 1.5-4.7, P=.94). However, 26% of women who had preterm premature rupture of membranes had a matrix metalloproteinase-8 concentration above the 90th percentile (8.7 ng/mL), compared with only 10% of term controls (odds ratio 3.1, 95% CI 1.1-8.7; P=.03). Elevated matrix metalloproteinase-8 remained associated with preterm premature rupture of membranes after adjustment for maternal age, race, parity, gestational age, and year of amniocentesis (odds ratio 3.4, 95% CI 1.2-9.9; P=.03). Conclusions: The overall distribution of midtrimester amniotic fluid matrix metalloproteinase-8 levels did not differ between women who had preterm premature rupture of membranes and those delivered at term. However, marked elevations of midtrimester amniotic fluid matrix metalloproteinase-8 were highly associated with subsequent preterm premature rupture of membranes, suggesting that the pathophysiologic processes that contribute to preterm premature rupture of membranes may begin in early pregnancy.

and this:

Human neutrophil collagenase (matrix metalloproteinase 8 ) in parturition, premature rupture of the membranes, and intrauterine infection

MAYMON E.; ROMERO R.; PACORA P.; GOMEZ R.; ATHAYDE N.; EDWIN S.; YOON B. H.

Perinatology Research Branch, National Institute of Child Health and Human Development, ETATS-UNIS
Department of Obstetrics and Gynecology, Wayne State University/Hutzel Hospital, ETATS-UNIS
Department of Obstetrics and Gynecology, Seoul National University, COREE, REPUBLIQUE DE

OBJECTIVES: The mechanisms by which microbial invasion of the amniotic cavity leads to membrane weakening and rupture are poorly understood. Recently, endogenous host enzymes have been implicated in this process. Matrix metalloproteinases are a family of potent enzymes that degrade components of the extracellular matrix. Collagen type I provides the main tensile strength of the fetal membranes. Matrix metalloproteinase 8 (MMP-8), or neutrophil collagenase, degrades interstitial collagens, acting preferentially on collagen type I. This study was undertaken (1) to determine whether MMP-8 is present in amniotic fluid and whether its concentrations are changed in preterm and term labor and membrane rupture with and without intra-amniotic infection and (2) to determine whether the amniotic fluid concentrations of MMP-8 in labor at term are different in the lower and upper uterine compartments. STUDY DESIGN: A cross-sectional study was conducted and transabdominal amniocentesis was performed in women in the following categories: (1) midtrimester (n = 25), (2) preterm labor in the presence and absence of microbial invasion of the amniotic cavity (n = 86), (3) preterm premature rupture of the membranes in the presence and absence of microbial invasion of the amniotic cavity (n = 51), (4) term patients in labor and not in labor (n = 51), and (5) term premature rupture of membranes (n = 20). Additional paired samples of amniotic fluid were retrieved by transabdominal amniocentesis (upper compartment) and transvaginal amniocentesis (lower or forebag compartment) from 14 term patients (28 samples) in spontaneous labor with intact membranes. Amniotic fluid MMP-8 concentrations were determined with a sensitive and specific immunoassay. RESULTS: MMP-8 was detected in 95.4% (249/261) of all samples. (1) Spontaneous human parturition was associated with a significant increase in amniotic fluid concentrations of MMP-8 in both term and preterm gestation. Term (no labor median, 3.3 ng/mL; range, <0.06-38.6 ng/mL; vs labor median, 16.6 ng/mL; range, 0.33-1650 ng/mL; P <.05). Patients with preterm labor who delivered preterm (in the absence of microbial invasion of the amniotic cavity) had a significantly higher median amniotic fluid MMP-8 concentration than those with preterm labor who delivered at term (preterm labor, term delivery median, 3.1 ng/mL; range, <0.06-415.1 ng/mL; vs preterm labor, preterm delivery median, 32.5 ng/mL; range, <0.06-6006.6 ng/mL; P <.003). (2) Spontaneous rupture of membranes in preterm gestation but not in term gestation was associated with elevated amniotic fluid concentrations of MMP-8. Preterm gestation (preterm labor, intact membranes median, 3.1 ng/mL; range, <0.06-415.1 ng/mL; vs preterm premature rupture of membranes median, 35.1 ng/mL; range, 0.71-1184.1 ng/mL; P <.05). Term gestation (intact membranes median, 3.3 ng/mL; range, 0.24-38.6 ng/mL; vs rupture of membranes median, 5.6 ng/mL range, 0.22-19.8 ng/mL; P =.9). (3) Microbial invasion of the amniotic cavity was associated with a significant increase in amniotic fluid MMP-8 concentration in patients with preterm labor and intact membranes, as well as in patients with preterm premature rupture of membranes. Preterm labor (no microbial invasion of the amniotic cavity, preterm delivery median, 32.5 ng/mL; range, <0.06-6006.6 ng/mL; vs microbial invasion of the amniotic cavity median, 208.1 ng/mL; range, 4.2-14,600 ng/mL; P<.001).

American journal of obstetrics and gynecology (Am. j. obstet. gynecol.) ISSN 0002-9378 CODEN AJOGAH

and a bit of help from wikipedia, on “metalloproteinase”:

The collagenases are capable of degrading triple-helical fibrillar collagens into distinctive 3/4 and 1/4 fragments. These collagens are the major components of bone and cartilage, and MMPs are the only known mammalian enzymes capable of degrading them. Traditionally, the collagenases are #1, #8, #13, and #18. In addition, #14 has also been shown to cleave fibrillar collagen, and more controversially there is evidence that #2 is capable of collagenolysis. In MeSH, the current list of collegenases includes #1, #2, #8, #9, and #13. #14 is present in MeSH but not listed as a collegenase, while #18 is absent from MeSH.

so now i know that there may be a genetic factor (mthfr) and/or a physiological factor (the proteinases are enzymes) at work. the genetic factor can be tackled by folic acid. but the enzymes? no idea. must ask more about collagen structure and ways to strengthen it. and about enzyme testing — if such a thing exists and/or is possible — and at what stage.

the most interesting tidbit i gleaned while reading is that amniotic fluid is typically without white blood cells, so any response to infection (maybe only if the sac hasn’t broken? that makes sense, but i don’t actually know) comes from the baby. it’s such an interesting glimpse  into the mother/baby relationship during gestation.

dr l is pretty adamant that i need to wait three cycles before trying again. i am pretty adamant that one (now passed) is plenty. he has research on his side. i have nothing much on mine. except, perhaps, a little more control (!?) over when to get on with it.

so we agreed to wait for divine intervention another opinion: dr s, the not-so-researchy, has-a-few-people-skills perinatologist that i have now been referred to. i have promised to abide by what he says. ( if for some reason he thinks three cycles is NOT enough, i will quickly forget i ever made such a promise.)

dr l thought this was a great compromise, since he figured i wouldn’t get in to see dr s for at least a month, which would put me close to my third cycle anyway. but crafty me: i got an appt for december 4. which would be in time to catch cycle #2. which would make me very, very, happy.

in the meantime, i have been ok’d to dose up on 400 IU vitamin e; 1000 mg vitamin c (no linus pauling prescription doses for me, i guess); and whatever i want to take for folate. that one, really, just cracked me up. the difference between 400 mcg and 4 mg — that is, the difference between a standard prenatal dose and a megadose for mthfr patients — is pretty big, at least the way i do the maths. but the difference between 400 mcg and 1 mg — the difference between what i took with ruby and what i took with mairin — is, according to dr l, “clinically insignificant,” especially since i’m not starving to death on non-folate-supplemented food. “for all i know,” dr l smiled at me, “you get way more than you need just from your diet.” it’s true that we eat pretty well in our house, but still. that seems more sunnily optimistic than medically reasoned. oh well.

duirng our chat dr l did focus a bit on the “clinical insignificance” of my ruby-dose, though, which is about as reassuring as anything can be. (that is, not reassuring at all, but still recognizable as an attempt at reassurance, and also recognizable as information that should be reassuring, so there is something nice-if-not-reassuring about his having said it.) so i’m taking about 1.6 mg, which everybody agrees is low enough to be safe but high enough to help me feel better.

in the meantime, as we prepared our house for guests over the weekend and dug through still-unpacked boxes of bathroom linens and toiletries, i found two unused hpts. we’re set. for whenever.

many women in situations like mine — all of the various situations that can be considered “like mine” — find themselves glued to keyboards and screens looking for answers. and it’s wonderful, and it’s hard, because the beauty of having so much information at your fingertips is countered by the sheer ugly bulk of too-much-mis-information popping up in the search engine. but we keep at it. at least i do. (it’s part of the addictive personality, i guess.)

my latest forays have left me wondering whether i have the homozygous MTHFR mutation.

now, like most of my self-diagnoses, this one is lousy and uninformed. but i cling to anything that looks like a reason for recurrent pprom, and if i find anything that resonates with my experiences, well, then, i hang on all the tighter.

the one that gets me about this possibility is something my last ob said (before we moved out of state and so had to change docs). it went something like this:

“you know, i was at a conference recently and heard a talk about a genetic mutation that can cause prom. it’s expensive to test for, but the treatment is a megadose of folic acid. and since folate is good for you while pregnant anyway, why don’t you dose yourself up. take 1 mg a day.”

well, i thought this was a big deal, since 1mg is so much more than the 400 mcg typically recommended (even though many prenatals have higher doses). and i really thought it was a big deal when i went to buy 1mg pills and found out that that is considered a prescription strength. (i got around that by buying 400 mcg tablets and cutting a bunch of them in half.) and i took those extra pills faithfully, every damn day i was pregnant with mairin. and voila.

when slim came along and i met my new doctor, i gave him my shorthand version of my old ob’s prescription. new doc (dr. l) told me that 1mg isn’t really that much of a megadose, but sure, i could go ahead and take it. stupid me — i read into this that it wasn’t that essential. so sure, i took my folic acid like a good little mommy-to-be, but i didn’t go out of my way to dose myself up.

one of the sickest aspects of grieving is guilt. and guilt i’ve got by the gulletsful over this one. if i’d taken all that extra folic acid would ruby still be with us? i’ll never know. but i thought mr. google might be able to help me find out.

so it is that after many searches and links and related hits i ended up learning about mthfr.

like all my medical knowledge, i know about mthfr only enough to be a danger to myself. most interesting to me, though, is that some women who are prescribed folic acid for it take up to 4 mg a day. that’s a whole lotta folate. is there a toxicity level? what happens to a non-mthfr woman who takes this much? and even without the mthfr mutation, could such a high level help prevent pprom?

and the $10,000 question: how do i muster the courage to call dr. l and say, yet again, “so, i’ve been reading, and have this really wacky idea…”?