Recurrent Early Pregnancy Loss - 5 - Introduction to Immunologic Causes
Sunday, April 01, 2007
Kenneth F. Trofatter, Jr., MD, PhD
Under ‘normal’ conditions, our immune systems are designed to protect us from things that are foreign to our bodies and also to recognize that which is ‘self’ and allowing it to elude immune destruction (‘tolerance’). There are many components of the immune system. The first line of defense is the ‘innate’ immune system. This is comprised of cells (macrophages, neutrophils, natural killer cells), cytokines (chemicals produced by these cells), and one arm of the complement system that are capable of ‘recognizing’ something foreign, limiting its invasion, and eliminating it but without necessarily producing a specific memory for the immune response to the invader. This is sometimes referred to ‘nonadaptive immunity.’
The other side of the immune system results in the production of specific antibodies (made by B-lymphocytes) and clones of T-lymphocytes, also directed against the specific invader, that are capable of ‘remembering’ the invader and, therefore, can more quickly respond if they are attacked again by the same (or in some cases, a similar) organism. This ‘specific’ immunity is often termed 'adaptive immunity.’ When tissue destruction occurs, as the result of either a specific or a nonspecific immune response, the blood clotting system is often activated as well. This may help to ‘finish off’ the invading organism or limit its access to oxygen and spread throughout the body by clotting off the blood supply at the site of the battle. This is the ‘synergy’ between the immune system and the blood-clotting system referred to above in the first paragraph.
The implanting embryo inherits and expresses characteristics from both the mother and father. Although certain major ‘transplantation antigens’ are not expressed on the invading placental tissues, the maternal immune system, both nonadaptive and adaptive, appears to be able to recognize the fetal tissues as ‘foreign’, but in a way that facilitates, but limits, the invasion, permits remodeling of the spiral arterioles of the endometrium, and then 'tolerates' the persistence of these fetal tissues, lining the spiral arterioles and the placenta itself, throughout the duration of the pregnancy. It would appear that if the maternal immune response either under-reacts or over-reacts, the implantation, placentation, and ultimate survival of the fetus are in jeopardy. The balance is both remarkable and delicate. As we have mentioned in one of our earlier posts on the subject of miscarriage, a proper maternal immune response requires some degree of ‘education’ and this might only come at the expense of an otherwise ‘normal’ embryo, accounting for the high frequency of ‘first pregnancy’ miscarriages in early pregnancy and perhaps the higher incidence of pregnancy-induced hypertensive disorders (preeclampsia) more often seen in first pregnancies that survive the first trimester.
In the next post, we will address specific abnormalities of the maternal immune system and clotting system that may be related to recurrent early pregnancy loss…
33 Comments:
At Mon Apr 09, 10:03:00 AM 2007,
Tracey said…
Hi I have had 4 miscarries 3 of them are known that there is a blood collection at 30ml appox in the uterus.
Doctors have stated that this blood is a high chance of the miscarries but are unable to tell me why it is there or where it has come from i am an O negitive and my partner is an O positive due to those reasons when i start bleeding at appox 9 weeks they give me a injection of Anti-D Please note that in last 3 miscarrages the blood collection has first appeared at 8 Weeks Im in need of info after having 3 miscarries and getting no answers.
Thank you for your time and hope to hear from you soon
Tracey
At Thu Apr 19, 10:25:00 AM 2007,
mandy said…
i have also miscarried 4 times can anything be done to prevent this i have 2 healthy children but after my youngest i have not been able to carry past 7 weeks can anyone help me
Amanda
At Sat Apr 21, 12:49:00 PM 2007,
tiff said…
I am the same as you Mandy. I thought after two kids it would be easy to concieve. I'm in the midst of my second miscarraige, and I don't know if I can do this again. I have to go in for bloodwork analyisis, to see what's going on. How about you?
At Thu Apr 26, 05:10:00 PM 2007,
Kenneth F. Trofatter, Jr., MD, PhD said…
Thanks to all of you for reading and for your good questions. Tracey, I sent an email directly to you in response to your concerns, so I hope that answered your questions. For those of you who want to know more about what it means to be Rh-negative, I would suggest you check out a post I wrote on 2/14/2007.
As for Mandy and Tiff, my first questions would be if the father of your living children is the same person who fathered the pregnancies you have subsequently lost and have you developed any new medical problems since you had your successful pregnancies? In the meantime, you might want to check out my follow-up posts on the subject of recurrent early pregnancy loss addressing evaluation and therapy of this problem (4/8/2007; 4/12/2007; 4/14/2007). These at least will give you a place to start!
At Thu Apr 26, 05:58:00 PM 2007,
Healthline said…
Here are the posts Dr. Trofatter refers to in his previous comment:
2/14/07 Implications of a "Negative" Blood Type
4/08/07 Recurrent Early Pregnancy Loss - 9 - Evaluation
4/12/07 Recurrent Early Pregnancy Loss - 10 - Empiric Treatment
4/14/07 Recurrent Early Pregnancy Loss - 11 - Therapeutic Interventions
At Wed May 02, 03:34:00 AM 2007,
sexylady said…
i hav had 2 miscarriages maybe 3 since nov 06.had 2 hav a d&c on the 1st as the baby wasn,t comin away naturally.have been tryin since nov 05.had 2 children trom a previous partner with no probs.my current partner has children from a previous partner.can,t understand why im unable to carry.im only just 30.so its not likely 2 b my age.
At Thu May 03, 06:13:00 PM 2007,
Kenneth F. Trofatter, Jr., MD, PhD said…
Hi Sexylady,
Among the many questions I would ask under these circumstances are: How long ago did you have your first two children? Have you developed any medical problems since then? Has your weight gone up or down much? Do you still have regular periods? Have you developed more pain/cramping or heavier bleeding with, or between, your periods? Are you a smoker?
It might just be "your age" and you could have simply had two consecutive chromosomally abnormal babies that didn't carry. But, it also could be due to the fact you have a new partner. We have known for many years that when some women change partners, their immune systems may not recognize the pregnancies by that partner properly at first and this can result in pregnancy loss or poor growth of the placenta. Consequences of these events put women with new partners at increased risk for small babies and preeclampsia (pregnancy-induced hypertensive disorders). If the next baby miscarriages, I would suggest you see a specialist in Reproductive Endocrinology and Infertility to begin a good work up. There are lots of other possibilities I did not mention, but might be discovered by answering some of the questions I asked above.
Thanks for your question and keep reading! Good luck to you...
At Mon May 07, 11:25:00 AM 2007,
Anonymous said…
Hi. I have had two misscaraiges in the last four months both at about 7 weeks. I do have one child from my fisrt marraige. I am just wondering is it too soon to start testing on my husband and I too see if there is something preventing us from having a baby? Alot of women misscarry and I dont want be paranoind. Should we try one more time...and maybe wait a longer period of time to start trying? I have heard some doctors say theere is no reason to wait and others who say to wait 6 months to a year. I would love to get some feedback on this. Thanks!
At Tue May 08, 09:19:00 PM 2007,
Kenneth F. Trofatter, Jr., MD, PhD said…
Has he ever had any children? Keep your chin up. I usually tell women to wait 2-3 months, especially if they have had a D&C. If you have another miscarriage, find someone with an interest in recurrent pregnancy loss in your area. I bet you'll be okay!
At Wed May 09, 07:44:00 PM 2007,
sondra said…
I too have had 4 miscarrages all in a row. These pregnancies have been with my new hubby. I have two children from my first marriage and I had no problems. The plot thickens- I am 40 now and 6wks PG. I have been told I have a translocation problem. Something with T13 and T14. I am not sure if I understand but it lowers my chances of carrying to term to 50%. Can you give me more info on this? I was not planning on getting PG again but since I am I want this baby! I pray I can...
At Fri May 11, 11:11:00 AM 2007,
Kenneth F. Trofatter, Jr., MD, PhD said…
Hi Sondra. If you have a 'translocation' involving chromosomes 13 and 14, it is most likely what is termed a "Robertsonian translocation." Robertsonian translocations are relatively common and are found in about 1 in 1000 individuals in the general population.
This means you have the right TOTAL amount of chromosomal material (the quivalent of two chromosomes 13 and two chromosomes 14), but one of your chromosome 13s has become fused to one of your chromosome 14s.
Because you have the right total amount of genetic material, you are normal. The problem arises, however, when you make eggs (oocytes). Some of the eggs that you will produce will have the right total amount of genetic material as well, and others will not. When those that do not get together with 23 chromosomes from the father of the baby, you will end up with a baby with too little or too much genetic material. Most of those pregnancies will be lost early in pregnancy, but a small number may survive and produce a baby with both physical and mental abnormalities.
Genetic diagnosis of the baby is usually advised in ANY pregnancy conceived in a union where either parent has a translocation. Alternatively, you might consider consulting a specialist in Reproductive Endocrinology and Infertility. Through in vitro fertilization, you could produce a bunch of embryos that could be screened by a procedure called "preimplantation genetic diagnosis (PGD)" to look for chromosomal imbalances BEFORE putting the, presumably, normal embryos into your uterus to grow! At your age, that might be your best bet, although it WILL be expensive. Otherwise you can just keep taking your chances and sooner or later may 'get it right' again!
At Mon May 14, 02:16:00 PM 2007,
Anonymous said…
Hi everyone. My name is Christine i'm 20 years old and 6 weeks pregnant. I have been with my boyfriend for 4 years now, and we are not ready for a baby. We had a problem with the condom we used and i fell pregnant. I am starting to experience bad cramps in my lower stomach which feels like a bad period pain. Have i got anything to worry about. Please Help.!
At Tue May 15, 10:15:00 PM 2007,
Anonymous said…
Hi im 26 years old i had a misscarriage today May 15 2007 i have been really upset but im dealing with it. I have been married since september and we have been trying to have a baby ever since I have a 4year old beautiful daughter who graduated from preschool today so when i found out was pregnant i never imagined i would misscarry.
At Wed May 16, 06:43:00 AM 2007,
Kenneth F. Trofatter, Jr., MD, PhD said…
Hi Christine. At six weeks, your doctor should be able to see if there is a baby in the uterus and if the baby is alive. Bad cramping could be an early sign of miscarriage, or a sign that the pregnancy is not in the uterus but in a fallopian tube (ectopic pregnancy). If the cramping continues, or if you start having some bleeding or more staedy pain, you should let your doctor know. Good luck!
At Wed May 16, 10:16:00 AM 2007,
Kenneth F. Trofatter, Jr., MD, PhD said…
Hi 26 year old. I am so sorry about your loss. The best thing you have got going for you is that you have previously had a baby successfully. I have found that it is not unusual to miscarry the first baby with a new partner, just like it's not that unusual to carry a true first pregnancy. Give yourself a few months, start taking some prenatal vitamins and try again. Bet things will work out just fine in the end!
At Sat Jun 23, 12:11:00 PM 2007,
Anonymous said…
hi, I'm 36 years old. I had a miscarriage at 13 weeks in Nov 06 and one in May 07 17.5 weeks. Doctor has advised that cells from my placenta and cells from my babay's skin did not grow in tissue culture. Will I be able to have a healthy child in the future?
At Tue Jun 26, 10:18:00 AM 2007,
Kenneth F. Trofatter, Jr., MD, PhD said…
Dear Anonymous: If you lost babies at 13 and 17 weeks, this is most likely the result of chromosomal abnormalities, some other genetic condition, or a serious underlying medical problem on your part (although the latter is less likely than the first two uless you know you have such a condition already). The fact the cells could not be grown in culture increases the risk of one of the first two problems. I cannot answer your question about likelihood of carrying the baby because we do not have the information about the babies' karyotypes. I will suggest that you consider having chromosmal studies done on both you and your spouse because these midtrimester losses are more often associated with fetal chromosomal abnormalities resulting from a parents who themselves have balanced translocations and chromosomal inversions. If you or your spouse has one of these, a genetic counselor will be in the best position to apprise you of your risks and chances for a chromosomally normal/balanced baby. Good luck and thanks for reading!
At Mon Jul 09, 05:39:00 PM 2007,
Tai said…
I am 23 yrs. old and have been with my husband who's 24 yrs. old for a toltal of 7 yrs. (we've been married for 4.) Although we never wanted to have any children as of yet, we didn't do anything to prevent them and i have concieved and miscarried 10 times, throught the course of 6 years. We decided to see a fertility specialist and he performed a series of painstaking test and every thing came back mormal. He suggested that we see a hemotologyst, which we will be seeing this coming Wednesday. I have never heard or seen a case like mine and I feel very alone, especially when all of my friends already have children and could in no way relate or understand the pain I have been through. For the past 8 months my husband and I have been using contraceptives to prevent from having any children until we resolve this problem. I'm nervous about my appointment and cannot think of any questions to ask my doctor,I'm also affraid of not being able to find a solution to my problem. Any suggestions? Any words of comfort?
Yours Truly,
Misunderstood Tai.
At Fri Jul 13, 06:52:00 AM 2007,
Kenneth F. Trofatter, Jr., MD, PhD said…
Response to Tai: Do you know what kind of studies your 'infertility specialist' did and what the results were? I am curious as to why they are sending you to a hematologist? Were all your miscarriages early and were babies ever seen before you miscarried? I have had several patients like you over the years and every one of them eventually were successful in having a baby. If no obvious reason for the miscarriages is identified, you probably have an underlying immunological barrier to carrying a pregnancy or you and your partner share a lethal combination of 'recessive' genes that together decrease your risk of a successful outcome. I would suggest you seek out an 'infertility specialist' who has a special interest in recurrent early pregnancy loss to discuss your options. Personally, I would offer you a full-court press of empiric therapy (see may later post in this series on that subject) if you have not yet tried that approach. I wish you luck and I am sure this has been difficult. It makes good sense not to conceive again until you have completed your 'work-up.' Thansk for reading.
At Wed Aug 15, 03:31:00 PM 2007,
Anonymous said…
Hi. I'm 27 and i wanna find out if i'm pregnant. I already bought 2 tests and both of them said "negative". However, i haven't had my period and i'm more than a week late. I'm not regular and had sex without condom on day 10th, and i had the after pill. Is there a chance ive got ectopic pregnancy? Or am i pregnant at all? Besides, i take the after pill many times before that... Help!!!!
At Fri Aug 17, 12:48:00 PM 2007,
Kenneth F. Trofatter, Jr., MD, PhD said…
To Anonymous August 15: It does not sound like you are pregnant at all (at least I hope not). The home pregnancy tests are usually very reliable. However, if you have not started a period in two weeks, either repeat the test or have your doctor send a blood test. You really ought to use use something for contraception in the interim if you don't want to get pregnant! Sometimes taking the "morning after pills" will alter your normal menstrual cycle. Of course that means you will have NO IDEA when you might ovulate again and possibly get pregnant. By the way, I DO NOT recommend using the "morning after pill" approach as your primary means of contraception. It is NOT foolproof. Why don't you try using BOTH a condom and going on regular use of a good oral contraceptive to reduce your risk for both pregnancy AND sexually transmitted infections! Good luck and thanks for reading! Dr T
At Mon Sep 03, 04:13:00 AM 2007,
Seema said…
I am 31 years old. I have a son who is 4 years old. I have had 3 miscarriages. With my first pregnancy, I had bleeding just at 4 weeks for 3 hours and it stopped, and the pregnancy test came positive. We waited for up to 8-9 weeks and there was no heartbeat. it was a twin pregnancy. there was fetal pole but no cardiac activity. the doctors said it was a missed abortion and i had a D&C. the biopsy results came back as hydropic abortion. My second pregnancy was uncomplicated and i delivered a boy. Again the third time, i had severe cramping at 7 weeks and it was threatened abortion, which subsequently miscarried completely. The fourth pregnancy there was very good heart beat at 6 weeks 4 days, but when i went after 10 weeks for a scan, they said the fetus stopped growing at 7 weeks 4 days and they evacuated it. all these pregnancies are with the same partner. I had so many blood tests done including antiphopholipid antibodies, anticardiolipin antibodies, lupus anticoagulant, antithyroglobulin antibody, toxoplasmosis, cmv virus etc. and everything came back negative.
Now i am pregnanat 10 weeks and 3 days. I had a scan whch showed the baby grwoing very nicely corresponding to 11+ weeks. i haven't had the genetic testing done. My doctor has put me on low molecular weight enoxaparin 20 mg subcutaneously starting from 4 week 3 days and low dose aspirin and folic acid. My doctor said if I have some other immune disorders, then it can cause recurrent miscarriages and that enoxaparin will be helpful.
My questions are: If i am having such immune problems, how could i have delivered my son? My doctor said such problems could develop at any time and in my case i may have developd it after my son was born. if it is true, then what happened to my first pregnancy, before my son was born? if i have an immune problem then will it be possible that it caused my first miscarriage and then for the second pregnancy it remained inactive, and then again got active during teh 3rd and 4th miscarriages? If enoxaparin will increase the blood flow to the baby, how will it help before 8 weeks, when there is no umbilicoplacental circulation? The enoxaparin is really expensive and I would like to know if there is any use in continuing it, in my case? Kindly address my concernrs. I will be really grateful to you. Thanks a lot in advance.
At Tue Sep 18, 02:56:00 AM 2007,
Anonymous said…
I am 31 and had a misscarriage at 16wks, the baby had died interuterine and this was found at a scan. They said the baby had died 1 week before at 15wks. I had a sucessfull CVS at 12.3wks and test results were fine. My nuchal measurement was 2.3 but my Pap A result was low. do you think my misscarriage was due to the CVS or Low Pap A result? or that the Docs will not be able to tell? I am worried for next time. Thanks Elaine
At Wed Oct 10, 10:55:00 PM 2007,
Bijili said…
Hi Dr.Kenneth,
I have been married for 13 years and have had 13 miscarriages so far.I have done many tests including Chromosomal Analysis. My results were 46 XX 21ps+...21ps+ is an increase in size of the satellites on one homologue of chromosome 21. My Husbands result was 46 XY qh+..The Karyotype shows an elongation of the long arm of the Y chromosome.
We also did another test called Th-1 type cytokine estimation. Nmae of the test TNF-a..the normal range was upto <200 pg/ml but my count showed 703.299.
We are so desperate to have a child.Could you please give me some advise as to why this is happening . I will be really grateful to you. Thanks a lot in advance.
Liz
At Mon Oct 15, 02:49:00 PM 2007,
Kenneth F. Trofatter, Jr., MD, PhD said…
To Liz Oct 10: 13 miscarriages and NO living children! I would really need to have more information about the studies you have had done and the results. I would also like to know what kind of therapies have been tried so far...
Dr T
P.S. If you would like me to respond to your email, please send that information to the Healthline query link.
At Mon Oct 15, 11:36:00 PM 2007,
Bijili said…
Hi..
My first comment to you was sent on the 10th of oct.I am sending you my tests and reports.
1.Test performed:
NK Cells(Clone NK-1)..result.Positive
TNF-a(Clone TF05)..result..High Positive
IFN-y(Clone G-30)...result..Negative
IL-2Receptor(Clone25C04)..Result...
Negative
HLA-G(CloneMCA2043)..Result...
Low Positive
Since my TNF-a level read 703.299 (Normal Range supposed to be <200 pg/ml) My Doctor here in India is giving me WBC injections. She uses my husbands blood separates the RBC and WBC and gives me those injections every 2 weeks .She said she is going to do this treatment 4 times.Then has asked me to conceive and then to do the same treatment.Right now my count has come down to 589.509 pg/ml.
The other test done was as I had mentioned before about my Chromosomal Analysis. My results were 46 XX 21ps+...21ps+ is an increase in size of the satellites on one homologue of chromosome 21. My Husbands result was 46 XY qh+..The Karyotype shows an elongation of the long arm of the Y chromosome. Both our results also said that this is a variant which is seen in the normal population but is also seen in patients with various indications.
Blood Investigations
Tests Patients Results
R.A.Test Negative
C3 118( Normal
range88-201)
C4 24.2(Normal
range 16-47)
ACA-IgG 5.3GPL Units
ACA-IgM 20.7MPL Units
(Since my count was a little more than normal I had a 6 month course of tablets )
Anti nuclear Antibody...method used Immunofluorescence
Result was Negative
Tests for LUPUS ANTICOAGULANTS
Tests Results
Prothrombin time 13 Secs
Activated Partial
thromboplastin time 32 secs
Kaolin Clotting time 75 secs
dilute Russel Viper
Venom Time 32 secs
V.D.R.L Negative
Platelet count 342*10/L
Comments after test were:L.A...Absent
Work-up regarding antiphospholipid antibody syndrome..results are negative.
These are all the results I have.Hope these will help you to give me some advise.Thank you for your time and hope to hear from you soon.
Liz
At Fri Oct 19, 07:14:00 PM 2007,
Kenneth F. Trofatter, Jr., MD, PhD said…
To Liz Oct 15: Thanks for getting back to me with your test results. I had a patient like you may years ago who only responded to white blood cell injections. She had had 10 documented miscarriages and I used pooled white blood cells from various donors, not just her husband. I imagine you have already tried other therapies as well such as prednisone, heparin, or low molecular weight heparin? Anyway, I really don't have any other suggestions at this point, but if the transfusions don't work, and you have tried the other things, I do have one really wild idea that might. By the way, are you and your husband closely related in any way? Good luck. Dr T
At Mon Oct 22, 08:12:00 PM 2007,
Bijili said…
Hi Dr T,
Thanks for opinion.My husband and I are not related.My Husbands blood group is O+ and mine is A+.I would like to know that wild idea. I will keep you posted once my treatment is over. Thanks a lot once again.
Liz
At Fri Oct 26, 04:18:00 PM 2007,
Kenneth F. Trofatter, Jr., MD, PhD said…
To Liz Oct 22; No really wild ideas until you've tried the one you are going through now! Let me know what happens! Dr T
At Tue Oct 30, 06:24:00 AM 2007,
Bijili said…
Hi Dr T
My Dr has suggested after this treatment of WBC injections I get pregnant.Once I conceive she has asked me to take heparin injections daily for upto 3 months,aspirin tablets orally and also progesterone tablets 200mg twice daily vaginally.What is your opinion regarding this ? Thanks a lot for your advise and I will keep you posted regarding my treatment and pregnancy.
Liz
At Mon Nov 05, 10:43:00 AM 2007,
Kenneth F. Trofatter, Jr., MD, PhD said…
To Liz Oct 30: That sounds good to me. Best of luck and let us know how things turn out! Dr T
At Sat Nov 10, 08:59:00 PM 2007,
Anonymous said…
HI I AM 23 I MISCARRIED 5 TIMES AND WOULD LIKE TO KNOW WHAT IS MY POSSIBILITIES OF HAVING AT LEAST ONE CHILD. I DID ALL THE POSSIBLE TEST THERE IS AND EVERYTHING CAME BACK NORMAL/
At Tue Nov 13, 05:44:00 PM 2007,
Kenneth F. Trofatter, Jr., MD, PhD said…
To Anonymous Nov 10: There are ALWAYS more tests that can be done and haven't been found yet to be associated with recurrent pregnancy loss. Even if nothing has been found, have your doctors tried anything to help you carry a pregnancy. There comes a time when empiric therapy is worth tryingg even if we don't know what we are treating. One of my last posts in this series talks about that approach. You are probably at that point with 5 miscarriages already. Best of luck! Dr T
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