Sunday, January 24, 2016

The other corticosteroid: dexamethasone [what my doc wants to put us on]

I was pleasantly surprised when we got the information about our most recent protocol (before our appointment with the doctor) that the doctor had indicated he would be proscribing a steroid—dexamethasone.  Dexamethasone, like prednisone, is a corticosteroid.  (20mg of prednisone is roughly equivalent to 3mg of dexamethasone.)  But I’ve read SO MUCH about the use of prednisone (or prednisolone) during pregnancy, and read very little about their cousin dexamethasone, so I was a little unsure why he picked dexamethasone over prednisone.

I had a very difficult time finding any medical journal articles comparing dexamethasone or prednisone for recurrent miscarriages.

One RE doctor’s website, when asked “The AEB center uses Dexamthasone, but I really do not know why the prefer it over the Prednisone” responded “90-95 percent of prednisone is broken down by the placenta , so very little gets to the baby. This is not the case with dexamethasone.”


Another blog suggested that dexamethasone was preferred on the front end, because it “calms” NK cells, while prednisone is preferred once pregnancy is established.


When I just limited my searching to the use of dexamethasone for miscarriage prevention, things got… interesting.  The first hit was an article about using dexamethasone to TERMINATE pregnancies (in dogs—it was jarring to read “bitches”).http://www.ncbi.nlm.nih.gov/pubmed/9404290  YIKES.  (Indeed, Google will suggest other searches you might like to run include “dog abortion.”  Jeez.)

Then I ran across an Atlantic article suggesting the use of dexamethasone during pregnancy has some pretty serious risks:


The article suggests that “prenatal synthetic glucocorticoid exposure could permanently change the way a person's genetics will operate over his or her lifetime.”  YIKES.  That applies to prednisone as well, too, although prednisone does not appear to cross the placenta as much as dexamethasone.  It reports that a Swedish study was halted because of severe adverse outcomes: “In mid-2012, the Swedish research team reported that they had gone to their ethics board to tell them they were shutting down their trial use. The Swedes have so far found 8 "severe adverse events" among 43 children exposed in utero. Problems among those exposed include mental retardation (3 cases among the 43 children), memory problems, and growth disorders.”

Also, it’s one of the steroids that can be used to speed up fetal lung development in case of risk of premature delivery: http://www.ncbi.nlm.nih.gov/pubmed/8960608

YIKES.  No good medical journal articles suggesting dexamethasone is beneficial to treat miscarriages—other than its grouping as a steroid generally—and some pretty scary suggestions that it may mess with the fetus’s development.

So I have a meeting with my RE before we start any procedure, and I’m going to get some answers about why he would suggest dexamethasone, what dosage and for how long, and his thoughts on prednisone.  I’m also going to give him one of the articles I found on prednisone.

Monday, January 4, 2016

Prednisone for recurrent pregnancy loss

After a number of pregnancy losses, including two with chromosomally normal embryos, I’m feeling a little desperate.

So I return to prednisone.  As I previously mentioned, when I got a second opinion from CCRM they said they put all of their hail Mary patients on prednisone. http://3yearwait.blogspot.com/2015/10/cheating-on-my-fertility-doctor.html?_sm_au_=iVVVVMV7JF6FqnsM  My doctor pooh-poohed the use of prednisone, emphatically insisting that he has never proscribed it.  But… what if he’s wrong?

“Immunotherapy” 

There is some suggestion that some miscarriages may be caused by an immune reaction (this article suggests potentially stress related?!). http://www.jimmunol.org/content/190/12/6051.full  (This particular article is too complicated for me to fully digest, but suggests at a high level that “The present study provides evidence that stresses might enhance the activity of glucocorticoids, leading to a miscarriage via the lipid mediator LXA4 pathway.”)

Here’s an article that goes through some of the popular options for women who have suffered from repeated miscarriages:

·        Aspirin (81mg, ie baby aspirin)
·        Heparin (Heparin 5000 IU twice a day or Lovenox 40 mg sq once a day or Fragmin is 5000 IU sq once a day, started 14 days before transfer for 12 to 34 weeks)
·        Prednisone (30 days before transfer)
·        Immunoglobulin G Infusion
·        Enbrel (25mg 2x/wk)
·        Paternal Leukocyte Immunization


I’m going to focus this post on prednisone.  And I’m going to focus just on the evidence that, as a general matter, prednisone can help (or not) with repeated miscarriages.  I will save, for another day (maybe, if I can slog through it), posts on natural killer cells / alloimmune implantation dysfunction / autoimmune implantation dysfunction / antinuclear antibodies / anti-thyroid antibodies / antiphospholipid antibody / antiovarian antibodies—things that may (or may not) be related to repeated miscarriages and things that prednisone may (or may not) help with.

What is prednisone?

Prednisone is a steroid that suppresses inflammation.  The body naturally produces around 5-10mg of prednisone a day.  In times of stress (such as surgery or trauma) for a short period it might produce as much as 25-30mg/day. 

Prednisone can be used to treat inflammatory diseases such as rheumatoid arthritis, but has significant side effects, especially at higher doses and when used for long periods.  Because prednisone naturally occurs in the body, additional amounts above 10mg are considered clinical doses that are more likely to have clinical impact.  Doctors can use lower doses, especially to maintain or control a disease.

Use of prednisone can suppress the adrenal glands.  (In other words, if you’re using prednisone, your body might stop making it naturally.)  When the adrenal glands are suppressed, the body may temporarily lose the ability to manufacture natural corticosteroids, which results in dependence on prednisone.  For use of less than about 3 weeks of use, prednisone does not do much to suppress the adrenal glands.  (Wikipedia says use of less than 7 days does not suppress the adrenal glands.)  Once prednisone has been taken long enough to suppress the adrenal glands, it should be tapered off slowly instead of abruptly stopped.  (In other words, if your body has stopped making prednisone naturally because you’ve been taking supplemental prednisone, you should taper your dosage off slowly to let your body start making it again.)

Prednisone is turned into prednisolone in the liver.  So some studies that discuss treatment options will discuss prednisolone. 

Prednisone can have some very, very serious and intense side effects.  Side effects of prednisone, even at low doses, include insomnia, heart palpitations, and increased appetite.  Even low doses of 5mg a day, there can be negative effects in terms of bone loss.  At higher doses, and over longer periods of use, it can have very scary and dangerous side-effects.  Doses of 24mg/day for more than 2 months is thought by some to be the threshold for significant side effects, such as osteoporosis.  And at larger dosages for longer periods of times, the risk and severity of side effects increases.

My information about prednisone is pulled from what I read on the internet and also what I learned from consulting with a rheumatologist.  Here are some of the articles I considered:


Articles suggesting prednisone could help with recurrent miscarriages

Some doctors have theorized that use of prednisone at doses of around 20mg from before implantation through the first trimester can significantly increase live birth rates after pregnancy.  (So it can’t necessarily get you pregnant, but it can keep you pregnant.)

Here’s an article about recurrent miscarriages, focusing on a women with NINETEEN consecutive miscarriages at between 5 and 12 weeks (devastating!); she eventually had success with prednisone:

Recurrent miscarriage (RM) is a distressing condition for which routine investigation fails to find a cause in 50% of cases

Thirty‐one percent of this patient’s endometrial cells were uNK cells. The control patients, who had had at least two live births, had 0.2–9.5% uNK cells in their endometrium and the other recurrent miscarriage patients in the study had 0.2–22% uNK cells

The patient decided that a trial of pre‐conceptual prednisolone 5 mg/day should be prescribed. Between 1999 and 2001 she suffered three further consecutive losses at 5–6 weeks of gestation, bringing the total number of losses to 19.

An increased dose of preconceptual prednisolone (20 mg/day) was taken for 6 months prior to conception in May 2002. The prednisolone was stopped at 5 weeks gestation after a home pregnancy test was positive. The pregnancy was monitored with serial ultrasonography and complicated by intrauterine growth restriction and oligohydramnios. 


There is evidence that after repeated miscarriages, prednisone could help:

Women with a history of IRM, defined as three or more consecutive miscarriages before 20 weeks' gestation without associated anatomic, cytogenetic, hormonal, and infectious pathologies or antiphospholipid syndrome. . . .  were treated with prednisone (20 mg/d) and progesterone (20 mg/d) for the first 12 weeks of gestation, aspirin (100 mg/d) for 38 weeks of gestation, and folate (5 mg every second day) throughout their pregnancies . . . .  The overall live birth rates of the treatment and control groups were 77% (40 of 52) and 35% (18 of 52) (P=.04).


The article notes that in their study the duration (starting before pregnancy through first trimester) and dosage (20mg/day) they saw good results with no side effects, contrary to other studies that have longer durations, start after pregnancy, or use smaller dosages:

This study demonstrates that a combination treatment consisting of prednisone, aspirin, progesterone, and folate results in a higher live birth rate than no treatment in women with IRMWomen who were treated with this combination had a 42% higher live birth rate than controls. In addition, we did not note a higher rate of preterm birth or intrauterine growth restriction among the treatment group. Our results are in accordance with previously reported data by R├ęznikoff-Etievant et al. (7) and others suggesting that prednisone treatment limited to the first trimester may be effective in the treatment of IRM, while not being associated with an increased rate of side effects, such as preterm birth or intrauterine growth restriction.

Others have reported no effect of corticosteroid treatment in women with recurrent miscarriages and IRM (8, 9). The difference between these studies and the data obtained by R├ęznikoff-Etievant et al. and our group might be due to both the dosage and the duration of corticosteroid use. Studies that were not able to assess a positive effect of corticosteroid treatment used low-dose treatment during the whole duration of pregnancy.

In contrast, a high-dose treatment covering the first trimester might deliver antiinflammatory protection during the most sensitive period. In addition, the treatment scheme used in our study aimed at covering the full length of early pregnancy by starting the treatment before pregnancy, whereas others started treatment after establishing a diagnosis of pregnancy (8, 9). Similar to folate neuroprotection, this strategy might severely limit the protective effect of corticosteroids.

It also notes that they did not see preterm birth or growth restriction side effects.

Another article suggests prednisone was effective in women with recurrent miscarriages (3 or more losses):

Eighty-one percent of the enoxaparin (46/57) group and 85% of the combination-treated group [prednisone, aspirin, and progesterone] (45/53) were delivered of live infants compared to 48% (24/50) of the placebo (P < 0.05). . . . Miscarriage rates were significantly lower in the treated groups compared with placebo (P < 0.05). There were no significant differences in late obstetric complications or neonatal mortality between groups.


This one says the same thing:


For women with 3 or more unexplained habitual abortions before 12 weeks, researchers evaluated them for antiphospholipid antibodies, antinuclear and antithyroid antibodies (autoantibodies were present in 33.9% of the patients) and then treated them with either aspirin alone (100mg for the first 7 months of pregnancy) or aspirin with prednisone (20 mg/day up to 12 weeks).  (They started with 678 patients.  66% of the patients were autoantibody-negative.  277 patients were treated, some were autoantibody-negative and some were autoantibody-positive.)

Patient population
Treatment
Live birth rates
63 autoantibody-negative
aspirin
74.6% (47 out of 63)
161 autoantibody-negative
prednisone and aspirin
90.7% (146 out of 161)
53 autoantibody-positive
prednisone and aspirin
84.9% (45 out of 53)

The authors concluded that “Prednisone and aspirin seemed to be as efficient in autoantibody-negative or positive women but better than aspirin alone in autoantibody-negative women. A double-blind trial is in progress to confirm these results.”  In other words, prednisone and aspirin worked equally well whether the women were autoantibody-negative or positive, and prednisone and aspirin was better than aspirin alone.  They started their protocol when they had a B-HCG measurement (positive pregnancy test). They did not find increased adverse outcomes in women treated with prednisone, noting that studies that did find adverse outcomes were for longer-term usage of prednisone.

I can’t get the full text for this one, but it suggests that treatment with IV immunoglobulin and prednisone starting from before ET and continuing in the first trimester helped women with repeated miscarriage (live birth rate of 61.5%):


And here’s another one I can’t get the full text on, saying use of prednisolone for women with recurrent miscarriage appears to be beneficial:


So there is a fair bit of evidence suggesting 20mg prednisone / day from before pregnancy through the first trimester can help women with recurrent miscarriages achieve a pregnancy.

Articles suggesting there is no evidence one way or the other

This is a very detailed article:


It suggests aspirin may help recurrent miscarriages in some cases and that prednisone may also help, but there is “no robust evidence”:

·        “There is paucity of evidence to make any recommendation on aspirin for treating recurrent miscarriage in women without antiphospholipid syndrome. . . . Aspirin is useful in many undiagnosed implantation failure patients. However, in the absence of strong evidence, routine use of Aspirin is not recommended (Evidence level II)”
·        “The effect of prednisolone therapy for some women with recurrent miscarriage may be due to altered endometrial angiogenic growth factor expression and reduced blood vessel maturation. The role is mostly limited to recurrent miscarriage with known connective tissue disorders. . . . There is no robust evidence to recommend steroid use for unexplained recurrent miscarriage.”

It further suggests that for women with hematological disorders, “Low doses of acetylsalicylic acid and low molecular weight heparin (LMWH) are the best solution in women suffering from recurrent spontaneous miscarriage.”

Articles suggesting prednisone does not help with increasing pregnancy

This article suggests that routine use of prednisone does not appear helpful: “Low-dose prednisolone treatment in addition to the standard protocol before and after embryo replacement does not appear to have a significant effect on pregnancy or implantation rates.”


In it, they used 10 mg/day of prednisolone in two divided doses starting on the day of ovarian stimulation and lasting for four weeks.

This one also suggests 5mg of prednisone plus 100mg aspirin did not increase pregnancy rates and increased risk of prematurity, although it seems like the prednisone was given starting after they were pregnant and given for the duration of the pregnancy:


So, these studies are different than the ones finding success in terms of amount, start, and/or duration.

Risks of prednisone while pregnant

For women with rheumatoid arthritis, the use of prednisone in the first trimester is associated with more adverse outcomes (pre-term birth and preeclampsia):


Yuck.  It does not say how much prednisone the women were exposed to or for how long, although the women are being treated for rheumatoid arthritis so presumably more than the low doses used by fertility treatments and throughout their entire pregnancy.  This is consistent with the studies discussed above that did not see increased adverse pregnancy outcomes when prednisone was only used in the first trimester.

The devil is in the details: when to start and how much to use

From what I can tell, clinics are all over the map in whether and how they will use prednisone.  My doctor, for example, told us he has NEVER proscribed prednisone.  At CCRM, as I previously mentioned, they use low doses once they have a patient with repeated IVF failure (as we have).  I have two friends who went to CCRM after repeated loss and both were put on prednisone during their cycles (where they did go on to have babies).  My friend was proscribed 10 mg of prednisone starting two days after transfer, which they start weaning slowly at 6 weeks of pregnancy.

I’ve read that some other clinics use it as a matter of course:


And here’s a site with over 2600 posts relating to the topic “Anyone on prednisone for recurrent loss??”:


(Answer, yes.)

Again, though, the devil is in the details.  When to start, when to stop, how much to use, etc. all matters.

From what I have read, it sounds like the safest procedure is to start 2-4 weeks before embryo transfer with around 10-20 mg and continue for the first 9-12 weeks of pregnancy, potentially starting to decrease the dose at about 6 weeks.