Recurrent Early Pregnancy Loss - 10 - Empiric Treatment
Thursday, April 12, 2007
Kenneth F. Trofatter, Jr., MD, PhD
If a woman has regular menstrual cycles and has never had trouble conceiving (and no abnormalities found during the diagnostic evaluation which is more often than not the case), I usually offer the following advice and empiric treatment regimen: discontinue smoking and alcohol and limit caffeine intake; begin a prenatal vitamin daily; start supplemental folic acid 4 mg daily; take a baby aspirin (81 mg) once daily (this antagonizes the ‘platelet side’ of the coagulation system); offer ‘progesterone support’ either in the luteal phase, or as soon as a pregnancy is confirmed and continue this until 10-12 weeks. I will also offer a course of a broad spectrum antibiotic (azithromycin or doxycycline) to BOTH partners early during the first cycle she attempts to conceive. These antibiotics treat organisms such as mycoplasma and ureaplasma (rather than culture for these organisms) among many others.
After conceiving, I ask that she return by about 6 weeks (two weeks after the missed menstrual cycle), perform an ultrasound to confirm an intrauterine pregnancy, repeat the lupus anticoagulant and anticardiolipin antibody screens (even if these were negative between pregnancies), and also screen for circulating complement levels. The complement system (the 'classical pathway') is activated by certain antibodies once they have attached to something ‘foreign’ (forming ‘immune complexes’) and help to destroy that to which the antibodies have attached. If complement levels are low or low normal during pregnancy (normally during pregnancy they increase), this might reflect ‘complement consumption’, the presumption being that the invading trophoblasts may be the targets against which the complement-fixing antibodies are directed. (Another possibility is that the 'alternative complement pathway', that does not require antibodies, is somehow being activated, but I do not want to get into that here and it doesn't change what I do at this point anyway!) I have used this approach (the low complement levels) over the years (although I have never seen a published study to justify it) to guide more aggressive therapy in women with known autoimmune disorders, lupus anticoagulants, or anticardiolipin antibodies, and even those with no other abnormal findings (the rationale being that there are things we still do not know, other factors which have not yet been found or implicated in pregnancy loss and, therefore, are not tested for at this time).
If the studies noted above are all ‘normal’, and the patient has a history of 3 or fewer losses, I recommend that no other therapy be started during this pregnancy. If the patient has had more than 3 losses, has previously failed this initial empiric approach to therapy, has any abnormal immunologic or coagulation studies, or just plain insists because "I want to do everything possible now," I offer to add either heparin (inexpensive) or low-molecular weight heparin (very expensive) therapy (which antagonize the other side of the clotting system), both of which must be given by subcutaneous injection. This regimen has replaced the immunosuppressive steroid (e.g., prednisone) therapy (except in the patient with an overt and active autoimmune disorder) that we used, also emprically, years ago when I first became interested in recurrent early pregnancy loss and it appears to be just as effective (with far fewer side-effects such as gestational diabetes, swelling, and increased risk for infection).
This approach to therapy is the foundation upon which I build for any woman with recurrent early pregnancy loss. In the absence of other specific abnormalities, 'success rates' are extraordinarily high using this approach. Others would argue that success rates in this group of patients are high regardless of what is done. I don't necessarily disagree with that, but I have had patients over the years who had far more than 3 losses who only successfully carried after starting this regimen, and quite frankly, I don't think any of us are smart enough at this time to know who actually needs it and who doesn't! In our next post let’s address what we do if specific abnormalities are found during the diagnostic workup, always keeping in mind that multiple factors may be in play and the 'empiric regimen' (or parts of it) might still be warranted, even after these other factors are addressed…
11 Comments:
At Wed Aug 01, 12:38:00 PM 2007,
Anonymous said…
Thank you for writing so much information on this subject. I just suffered my second miscarriage. The first was at 5 1/2 weeks, and this one was missed at 12 weeks (baby was only 10 weeks). We're waiting on pathology from the baby and are being referred to a geneticist.
At my 8 week appointment, the blood work came back positive (but inconclusive) for an antibody. I haven't been able to get specific information regarding this, but did ask to have a follow up screen. I am Rh + and my husband is Rh -. I'm worried it may be related to APS, but don't know who to ask about getting tested. Should I request a referral to an RE? Thank you for your help.
At Thu Aug 02, 12:43:00 PM 2007,
Kenneth F. Trofatter, Jr., MD, PhD said…
First of all, I am sorry for your losses. I would be curious to know what exactly you have been tested for and the actual results before making a recommendation about whom you should see next. If this was simply a "positive antibody screen" on your prenatal lab panel, counseling will be based on the specific antibody that is present. Those antibodies are directed against blood group antigens and some are not at high risk for causing problems. That antibody screen will not detect antiphospholipid antibodies. Also, wait until you get back a report on the baby. I am assuming they were going to try to do chromosomal studies. Talk to the geneticist and get back to me with any answers/questions you might have. Thanks for reading! Dr T
At Fri Oct 26, 01:05:00 PM 2007,
Nancy said…
I have just had my 8th miscarriage. All early and all "missed". 7 needed to be resolved with d&e's the last one needing 2 separate surgeries.
I am 44, and have 13 living dc so my doctor is just putting all of this to my age and has never suggested testing...just contraception and dealing with the losses that WILL come.
I am at a loss as to where to start with him and what tests to ask for...
He says my uterus is too scarred to support a pg. I know many women that have had more pg then I and yet they are not having a problem.
I guess I am wondering if it is worth it to push for the testing. And what tests to start with.
At Thu Nov 01, 06:39:00 PM 2007,
Kenneth F. Trofatter, Jr., MD, PhD said…
To Nancy Oct 26: Let me get this right- you have 13 living children and you have had 8 miscarriages (many with D&C's) and you are 44 years old and want more?????????? Your doctor is correct. The uterus has a limited number of sites to support implantation and between all of your pregnancies, and all of your surgical procedures, there probably aren't many places where a healthy pregnancy could implant. And, if it should, you are at extremely high risk for a placenta previa or a placenta accreta-both of which could be dangerous to you and a baby. Your risk for conceiving a chromosomally abnormal baby is also more than 1 in 10. I do not know any good reproductive endocrinologists who would think it was ethical to help you get pregnant at this point, although I am sure you could find one who 'practices on the fringes' and would be willing to take your money. I will be perfectly frank,why don't you quit thinking about pregnancy and enjoy your children and your grandchildren while you still can; or, consider adoption! Thanks for reading and for writing! Best wishes. Dr T
At Fri Nov 02, 07:51:00 AM 2007,
Anonymous said…
So, should someone with those "statistics" not get tested? What about conditions like MTHFR which can affect her future health? Just not test because she has so many living children already? How is that responsible medicine?
What would you say to me? I have had 19 losses (ranging from "chemical" to blighted ovum, missed miscarriage and ectopic) but only have 3 living children (2 deliveries) and am 32. Is my uterus too scarred despite having only had 2 D&C?
I feel blessed that I've encountered doctors who were willing to test, and sad that the only reason they do so is my lack of a large amount of living children and my age.
For what it's worth, they've never found a reason.
At Mon Nov 05, 05:58:00 PM 2007,
Kenneth F. Trofatter, Jr., MD, PhD said…
To Anonymous Nov 2: I am sorry if you thought my response was less than proffessional! I guess I assumed, perhaps falsely, that she would have already been tested for things that would most likely "affect her health" at her age ( e.g., diabetes, hypertension, hyperlipidemia, etc.) that would also be potentially correctable causes of pregnancy loss. One could spend an awful lot of money and could come up with no answers under these circumstances. By history, her losses are most consistent, not with a thrombophilia, but either aneuploidy (resulting from translocation or sporadically) or a genetic condition,for neither of which is there any treatment. The fact remains, that a pregnancy in her, even if it successfully gets beyond the first trimester is fraught with serious risks for both her and a baby with as many pregnancies she has had. So would any pregnancy you might have under the circumstances you describe, and you are not 44 years old. I am curious though, you say your doctors have not come up with any explanations, so does that mean they also have not tried any form of empiric therapy over the years either? To demand an explanation to justify 'treatment' in these settings makes us out to know more than we really do about recurrent pregnancy loss. We are actually quite stupid in this regard! Thanks for you comment. It is actually quite thought-provoking and does remind us of the challenges we still face in caring for women with RPL. Dr T
At Mon Nov 05, 06:15:00 PM 2007,
Sarah Elisabeth said…
Quote:
"To Nancy Oct 26: Let me get this right- you have 13 living children and you have had 8 miscarriages (many with D&C's) and you are 44 years old and want more??????????" end quote.
You're a disgusting individual. I wish your mother had decided she "didn't want more" before she had you.
SHAME ON YOU. You're talking to someone who just had a LIFE DIE INSIDE OF THEM. Perhaps you should consider a course in empathy before you continue using those letters after your name. Bedside manner goes a long way.
I'll be sure to let everyone know that you hold this attitude---BEFORE they come to you with their hopes in your hands. They should know you have a "limit" on how many children you'll help someone conceive. And, that you think some people should just shut up and suffer continuous losses.
Nancy wasn't asking for help to conceive---SHE WAS ASKING FOR HELP TO SUPPORT THE CHILDREN SHE ALREADY CONCEIVED. Just because you think she should stop having kids doesn't mean she deserves your snide attitude. Good to know you think human life is worthless if 13 other lives came before it.
At Tue Nov 06, 11:53:00 AM 2007,
Kenneth F. Trofatter, Jr., MD, PhD said…
To Sarah Elizabeth: My opening comment could have been left out, but I am sorry, you could not be more wrong about what I was trying to say to her. Pregnancy is a great risk to her and any more children (living and unborn) and there is no denying that fact. And, unless I cannot read at all, she is asking for help to have more pregnancies. I would like to know how a pregnancy that might cost her life is going to help her "support the children she already has." If you read her note, she "required two separate procedures" to recover from her most recent loss. These may well have been necessary because of a placental accreta. My "limit" is not the number of children someone can or should have, it is the risk and benefits related to those decisions. And, in the end, it's the patient who has to make the final choices. Not me. My only pledge is to provide as accurate information as I can and then support them the best way possible, regardless of the decision they make - even if it is contrary to my own opinion. If you think I have no empathy, I want you to consider the hundreds of hours I spend answering (at no charge) the hundreds of comments I get on this site; and, there are very few patients I have had over the past 25+ years who would share your opinion of my "bedside manner." But, you are certainly welcome to your own opinion. Dr T
At Wed Nov 07, 05:15:00 AM 2007,
Kenneth F. Trofatter, Jr., MD, PhD said…
To Nancy Oct 26: I AM SO SORRY. I could and should have expressed my thoughts in a more sensitive way. My brain tends to jump from A to Z and that can sometimes be an advantage in medicine and at other times we have to remember that all the letters in between are as important. One of the reasons I have such an interest in recurrent pregnancy loss is that my first three children ended in miscarriages and even after grieving and with the knowledge of probable reasons why, I still wonder to this day about what could have been...
Anyway, to answer your question, I would recommend the following in the way of testing if it has not already been done: screening for diabetes, hypothyroidism, hyperlipidemia, hypertension and basic liver and kidney function. Although you are probably at low risk, a general screen for autoimmunity (antinuclear antibodies, ANA) and perhaps antiphospholipid antibodies could be considered. I think the yield on the latter is low, but it might offer an explanation and identify you as a person who should be followed more closely over time for autoimmune disorders. It would help to know what if any studies you have had done to date and also if chromosomal studies were ever done on any of the pregnancies you lost. Your history is more one of having babies with chromosomal abnormalities rather than losses related to chronic disease or 'thrombophilia.' Chromosomal abnormalities can arise de novo and increase with age as the result of increased risk for nondisjunction, or they can result from babies that have unbalanced karyotypes resulting from a parent(s) with balanced translocations. I have posts on each of these subjects over the past year if you are interested. Parents with balanced translocations really do have to just keep trying because unless the translocations involve the same chromosome (which is not good at all, and could not be the cause in your case or you would have no normal children), a proportion of of your eggs (or your husband's sperm if he is the carrier) will result in a chromosomally 'balanced' baby - either completely normal or as a carrier of the same balanced translocation. You could find out if either you or your husband have balanced translocations, but it is expensive. There are still two reasons you might consider having that done: 1) it would provide you with an explanation that you are seeking; 2) if either of you is a carrier, you could then have your children evaluated for the same chromosomal abnormality. Those that had it would then be aware that they are at increased risk for recurrent miscarriage and babies with chromosomal abnormalities themselves.
Despite my lack of tact in my previous response, I am still greatly concerned for you and your risks for a future pregnancy and I did not want you to miss that message. The risks are very real based on what you told me in your comment. Again, I am sorry and I hope this helps...Dr T
At Wed Dec 05, 08:20:00 AM 2007,
daisy said…
I am not sure I am posting on the correct page... but here goes.
On Nov 5th, I suffered a missed miscarriage at 11wks 5days (gestational age=7wk 5d, which required an emergency D&C due to a suspect Molar Pregnancy. This is my 1st pregnancy, I am 36yrs old, regular 28day cycle, period lasts 4 days medium flow, nothing significant to note other than 5 sisters - all very very fertile.
Besides the obvious shock at facing into what I was told at the Early pregnancy clinic, I now want to ensure I understand what the histology report says.
The histology report results presented "no atypical features", but there are things I do not understand.
The clinical details: "Missed abortion @ 10/40. No foetal pole on ultrasound scan. ??Hydropic changes seen on scan."
The Macroscopic report reads: "a bulky amount of haemorrhagic products, 70x40x20mm's. No Membranes seen. No Foetal Tissue seen. Mp 2b SPE".
The Microscopic report reads: Chorionic Villi, inflamed and degenerate decidua, blood and fibrin, in keeping with retained products of conception. No atypical features seen"
Can you tell me in plain english what this means? We desperately want to have a baby and I'm concerned about maximising my success rates given the gynaecological challenges I could face at my age.
thank you for any help.
At Thu Dec 13, 02:31:00 PM 2007,
Kenneth F. Trofatter, Jr., MD, PhD said…
To Daisy Dec 5: Hi Daisy, sorry for your loss. From what you describe, you had a 'blighted pregnancy' that did not get past the very early stages of embryonic development, although the placental tissues continued to grow for awhile (which is not all unusual) and make pregnancy hormone (hCG) so that your body did not know the baby did not make it. It is very unlikely that you actually had a 'molar pregnancy', although that is what your doctors were concerned about based on the ultrasound. Hydropic degeneration of the placental villi are characteristic of molar pregnancies, but also of pregnancies undergoing spontaneous abortion if it has been awhile from the time the baby was lost to the time of miscarriage or if the baby was chromosomally abnormal. First pregnancies have a high rate of miscarriage for reasons I have detailed in my posts, but at your age, there is also a greater chance that the baby had a chromosomal abnormality. These are not uncommon and most babies with aneuploidy are lost in the first trimester. Your pathology report is not unusual under these circumstances - you had blood clot and the placental tissues were inflamed. The latter does NOT mean you lost this pregnancy as the result of an infection. It simply means that your immune system was reacting to the pregnancy tissues - that might be a good sign and increase your chance for success with a subsequent pregnancy. Hope this helped. Thanks for reading and good luck to you! Dr T
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