There is no single cause for recurrent miscarriages.
* Pregnancies miscarry at different times and there are different ways in which a miscarriage may occur.
* Briefly, they can be divided into several groups - genetic, hormonal, thrombophilic (blood clotting problems), anatomical (or structural), infective, and other causes.
* Many cases of recurrent mc will remain unexplained even after detailed investigations have been performed. It is important to understand that there will always be some couples whose pg losses remain unexplained. Importantly, the prognosis for a future successful pregnancy in the unexplained group is usually better than it is for couples in whom a recognised cause is identified.
In summary, no news of an abnormal test result is usually good news.
* The most common cause for a single miscarriage is a chromosomal abnormality of the fetus.
Chromosomes carry genetic information. The baby inherits half of its chromosomes from the mother & half from the father. Errors in transmission or division of the chromosomes can occur & lead too many or too few chromosomes. In many of these cases, the chromosome content is so out of balance that the pg mc's. It is important to stress that these errors occur randomly & are rarely a cause of recurrent loss.
In a small percentage of couples (3-5%), one partner possesses abnormal chromosomes which they repeatedly pass on to the fetus. The most common condition is when the chromosomes, although being of the correct number, are arranged differently. This is called a balanced or reciprocal translocation and is a recognised cause of recurrent loss.
If a parental chromosome abnormality is found, referral to a Geneticist, a doctor with a special interest in this field, will normally be offered. The chances of a successful pregnancy in the future will depend on the specific type of chromosomal abnormality.
It has long been thought that a hormonal (endocrine) abnormality underlies many cases of recurrent mc. Many theories have been suggested but so far none of them have led to treatments that have improved future pg outcome.
* Low levels of progesterone hormone are often found in women whose pg's are mc'ing. However, low progesterone levels in early pg reflect the fact that the pg has not implanted successfully, rather than because the developing placenta is not producing enough progesterone to maintain the pg. This is an important point - low progesterone is the effect not the cause of the miscarriage. This explains why giving women progesterone and/or hCG hormone injections in early pregnancy does not improve pg outcome. Progesterone blood tests in early pregnancy do not help to resolve the problem.
* An u/s shows that many women with recurrent loss have PCOS - polycystic ovaries. This is a common condition (affecting 25% of all women) in which there are multiple small cysts within the ovary. These cysts aren't dangerous and can't be removed because they are within the ovary. PCOS can be associated with a number of hormonal imbalances such as increased production of LH & testosterone. A number of carefully designed studies have shown that neither PCOS nor high LH levels are a cause for recurrent loss. The effect of testosterone and other androgens on the endometrium (womb lining) are currently being studied. There are therapies for this condition. If you want to read more on PCOS:
(There is also a board here for TTC with PCOS if you have been diagnosed with this condition).
* Follicle stimulating hormone (FSH) drives the ovary to start growing follicles. Sadly some women with a history of mc are also found to have high FSH levels because their ovaries have become prematurely menopausal. Although rare, this is obviously a very important problem to identify.
* Currently the only way of determining the response of the endometrium at time of implantation is to sample it and look at the histological (microscopic) evidence of the state of the tissues. This is why you may have an endometrial (womb lining) biopsy performed towards the end of your cycle (approximately day 26). This biopsy is no more uncomfortable than undergoing a cervical smear test. However, in order to be able to obtain the most useful information from the biopsy, you will need to collect some urine samples during the earlier part of your cycle, so that your LH levels can be measured to pinpoint the exact time of O. This enables the biopsy to be more thoroughly assessed.
* Further research is being done to determine the differences in the endometrium at the time of implantation between women with recurrent mc and those whose pg's have been successful.
Thrombophilic / Blood Clotting Disorders
The importance of blood clotting disorders in causing recurrent mc has now been firmly established.
* While it has been known for a long time your blood becomes thicker in pg, it has only recently been shown that this process is more pronounced in some women compared with others. If blood clots occur in the blood vessels of the placenta the blood flow to the baby is decreased and this can lead to either mc or, if the pg proceeds, to the birth of a baby that is smaller than he/she should be.
* Antiphospholipid antibodies, the 2 most important of which are the lupus anticoagulant & the anticardiolipin antibodies, cause blood to clot more easily. Women with a history of recurrent mc who have persistently positive tests for either lupus anticoagulant and/or anticardiolipin antibodies are said to have the Primary Antiphospholipid Syndrome (PAPS).
* 15% of women with a history of recurrent mc have PAPS. In pg's in which no drug treatment is given, women with PAPS have a 90% mc rate.
* Women with PAPS have a 40% chance of a successful pg when they are treated with aspirin alone but a 70% chance when treated with aspirin & heparin (a blood thinning drug which is safe for mother & baby). Subsequent studies have confirmed this high live birth rate with aspirin and heparin and as a result this has become, both nationally and internationally, the established treatment for recurrent mc sufferers with PAPS.
* While important advances in the treatment of women with PAPS have been made, many questions remain as to whether these antibodies affect the long term health of women.
* In addition to the antiphospholipid antibodies, the role of other blood clotting abnormalities, some of which are inherited, in causing recurrent mc is being investigated. There is a new method being pioneered, Thromboelastography (TEG), to assess blood clotting. The major advantage of this method for patients is that it requires only a small blood sample and the results are rapidly available.
Infection and Recurrent MC
* The role of vaginal infections in the causation of recurrent mc is a new field. Infection may well play a role in causing late pg losses (14 wks) in a small number of women but it is unlikely to be important in causing early mcs.
It is being investigated whether there is a link between an inherited predisposition to infection and recurrent mc and whether there is an association between specific groups of bacteria found in the vagina and pg outcome.
Structural abnormalities of the uterus and Cervical Incompetence
* Until recently there has been no simple, non-invasive way to reliably diagnose abnormalities in the shape of the uterus. This has changed. 3D u/s gives clear pictures of the shape of the uterus. It is very similar to an ordinary u/s.
* Cervical incompetence is often mentioned as being a cause of mc. It only affects pregnancies that have progressed beyond 14 wks. It is most commonly diagnosed on the history of there being a painless miscarriage and the insertion of a cervical stitch (cerclage) is often recommended. There is no reliable method to diagnose cervical incompetence and in practice it is an over-diagnosed condition.
* There is some evidence that women who smoke are at increased risk of mc and that this risk is related to the number of cigarettes smoked. Similarly, women with an excessive alcohol intake are thought to be more prone to have a higher rate of mc.
Above all, remember that it is likely that your next pg will be successful.
Recent guidelines from the Department of Health suggest that all women planning to TTC should take 400 micrograms of Folic Acid before pg until approximately 12 wks gestation. This is to prevent defects such as spina bifida rather than mc itself.
Thanks for the info, Beck.
Here is a link with lots of good information on anti-phospholipid antibodies. This includes anticardiolipin and lupus anticoagulant. These are antibodies that you may be tested for if you have recurrent m/c. These antibodies can cause blood clotting disorders as well as m/c and heart disease.
The above link does not include information about the other clotting disorders such as those caused by factor V Leiden and prothrombin mutations. For these thrombophilic disorders see the link below.
Another possible cause of recurrent miscarriages that I have not seen listed here yet is a genetic mutation in the gene coding for an enzyme that is important in metabolism. This enzyme is called methylenetetrahydrofolate reductase (or MTHFR for short). Mutations of this gene result in an enzyme the functions less effectively. The result can be that your body cannot convert folic acid to the form that is important for preventing neural tube defects. In addition, it indirectly causes an increased levels of a chemical called homoceistene in your blood. Homoceistene is usually converted into important amino acids, but in this case it builds up in your blood to toxic levels. This can cause heart problems as well as being toxic to the fetus.
The link below has various tests, conditions, and treatments involving recurrent miscarriage including MTHFR mutations.
Some details about genetic causes - aneuplody - trisomy - advanced maternal age:
For basic knowledge about aneuplody, trisomy and non-disjunction go to : http://en.wikipedia.org/wiki/Aneuploidy and http://en.wikipedia.org/wiki/Nondisjunction
Recurrent aneuploidy happens to some couples who produce chromosomally abnormal eggs or sperm not as a result of translocation but because they have a tendency toward non-disjunction. Non-disjunction means that wrong number of chromosomes is present in the embryo: Trisomy is the most common - 3 copies of chromosome, most known Down syndrome-3 copies of number 21 chromosome instead of 2 (in recurrent aneuplody this does not mean that the chromosome involved in the trisomy is always the same, that can vary), Monosomy: X with only one X chromosome (Turner syndrome). Polyploidity – too many extra sets of 23 chromosomes. (1)
* as many as 50% of early miscarriages are caused by chromosomal abnormalities in the fetus, nearly all of the chromosomal defects seen in sporadic miscarriages arise out of the blue (1)
* Study in Italy performed on 3000 women showed that calculated miscarriage rate was 15%, (6% for women less than 35y and 25% for women with more than 40y) With genetically analyze of all of the miscarriages they found that in the 40y incidence of chromosomal abnormalities was over 80%. (1)
*As older women reproduce, the frequency of aneuploidy goes up. This can be best appreciated by comparing the data from two studies of human miscarriages conducted 20 years apart; the proportion of miscarriages with trisomy has doubled (from 23% to 46%), almost certainly because of the change in the maternal age distribution(from average 28y to 34,7y). (5)
*Tendency to non-disjunction may be inherited or induced because environmental factors. At the present time we do not understand all the mechanisms that cause this problem, although we do know that the risk of trisomies increases with maternal age (1)
* It is also possible that some couples are at increased risk of abnormalities as a result of gonadal mosaicism, increased sperm aneuploidy in the male partner ... Recently, reduced total follicular number in the ovaries has been associated with increased risk for trisomy. An altered risk for trisomy in some individuals may also be the consequence of variants in proteins affecting DNA methylation or chromosome segregation during meiosis. For example, polymorphisms in genes involved in folic acid metabolism, as well as differences in folic acid intake, are possible maternal risk factors associated with Down syndrome (trisomy 21), although they were not found to be increased among women who had M/Cs involving trisomy. Mutations in hMSH2, a mismatch repair gene, have been associated with a significant increase in chromosomally abnormal sperm. Environmental factors, such as caffeine intake, have also been implicated as modifying risk for trisomy 21. (2)
* There are some reports that if our mothers were exposed to some chemicals we can have problems with chromosomally abnormal eggs: “exposure to low doses of BPA -bisphenol A during the final stages of oocyte growth [in female fetuses] disrupts meiotic chromosome behavior, resulting in the production of chromosomally abnormal eggs. Humans are exposed to BPA on a daily basis; it is a component of polycarbonate plastics, resins lining food/beverage containers, and additives in a variety of consumer products... BPA is only one of many chemicals with hormone-like actions, and our results suggest that low-dose exposure during fetal development has the potential to impact the entire cohort of oocytes produced by a female. Further, because this is a ‘grandmaternal’ effect (i.e. exposure of a pregnant female influences the genetic quality of the offspring of her female fetuses), documenting an effect of this type in humans would require studies spanning several generations.” (4)
Prognoses for future pregnancies:
The risk of you having another miscarriage after miscarrying a chromosomally abnormal pregnancy is very low, lower than risk of miscarrying again after you have suffered a chromosomally normal miscarriage, as chromosomally normal miscarriages are less random than abnormal ones (some other cause was responsible if the baby was chromosomally normal). (1) For example, one recent study has reported 29% of abnormal karyotypes in 167 patients with 3±16 M/C before 20 weeks. These authors found that after an aneuploid miscarriage, there was a 68% live birth rate for a subsequent pregnancy compared with 41% after an miscarriage with chromosomaly normal karyotype . (3)
Some natural ways to improve egg quality:(suggestions from different sources)
- a high protein/high fat diet, less sugar and carbs, no alcohol and coffeine helps with good egg development
- supplement with Co-Enzyme Q-10, which helps to support and improve mitochondrial functioning, the powerhouse of the cell. One of the hallmarks of aging is damage to mitochondrial DNA caused by oxygen metabolism and the presence of free radicals in the system.
- supplement with the antioxidants vitamins C, E, A, zinc, and selenium, B vitamins, and pycnogenol or OPC (oligomeric proanthocyanidins) to limit oxidative damage,
- supplement with powerfoods like supergreens (wheatgrass, chlorella, spirulina)
- suplements with L-Arginine helps increase blood flow to the ovaries (can be taken in food - for example fresh cooked turkey breast and whole almonds)
- Royal jelly
(1)Miscarriage – What Every Woman Needs to Know – A Positive New Approach Prof. Lesley Regan, 1997, 2001, second impression 2004
(2)The Origin of Abnormalities in Recurrent Aneuploidy/PolyploidyW. P. Robinson, D. E. McFadden, and M. D. Stephenson, Departments of Medical Genetics, Pathology, and Obstetrics and Gynaecology, University of British Columbia, Vancouver, Am. J. Hum. Genet. 69:1245–1254, 2001
(3) Chromosomal abnormalities and embryo development in recurrent miscarriage couples C.Rubio, C.SimoÂn , F.Vidal, L.Rodrigo, T.Pehlivan, J.Remohõ and A.Pellicer, Instituto Valenciano de Infertilidad, Valencia, Spain. Human Reproduction Vol.18, No.1 pp. 182±188, 2003
(4) Biochem. Soc. Trans. (2006) 34, (574–577)
(5) Scrambling Eggs in Plastic Bottles, R. Scott Hawley, Dorothy Warburton , PLOS Genetics Jurnal 2007
I just had a conversation with my doctor who recommended we do PGD (preimplantation genetic diagnosis), who gave me some interesting stats:
For those women over 35 who have experienced 3 or more losses, the percentage of having a miscarriage again is 87% (with IVF)
For those women over 35 who have experienced 3 or more losses and screen with PGD following IVF, the loss rate is only 12%
For women over 35, the average number of eggs with multiple, fatal genetic abnormalities is around 50% - having PGD can screen out any embryos with these fatal abnormalities
The age of the husband can also affect embryo genetic quality
Additionally, reproductive immunology is a relatively new field which explores more in depth issues such as anti-phospholipid antibodies, anti-cardiolipin antibodies & other clotting factors, natural killer cell activity and more. Go here for a quiz to determine the need for possible immunological testing:
Here is a video posted today by VegasMom which outlines causes (& fixes!) for recurrent pregnancy loss:
These are some interesting finding.
Thanks for the great info. I have a clotting disorder and that helped me figure out what all of this meant.
ps--my first three children were born healthy without the use of medication
Here is a link to a perinatal pathologist. God forbid any of us should have a m/c again!!! But, if it happens, and you agree to have a D&C, you can request a paraffin block sample of the placenta be prepared & ship it off to Dr. Salafia should you want a tissue study done. Our HMO agreed to do a karyotype but not a tissue study, since that's a very specialty field apparently and only a handful of doctors do this. Carolyn Salafia is one of them. She doesn't charge an arm and leg either.
Here is a link to Dr. Salafia's web site:
9 blessings - sorry to hear about your miscarriages :( If your doctor thinks baby aspirin isn't enough, you could take Lovenox. It's very expensive though. Hopefully you can get insurance to cover it should you take it. I tried taking Lovenox for my last pgcy, which I started CD6 I believe. However it made me bleed badly after implantation & continued until the doctor took me off the Lovenox early in the 1st trimester. This stopped the bleeding 100%. So now I am stuck with over $3000 worth of Lovenox... Lovenox anyone? :lol: I continued with the aspirin however, and for whatever reason ended up with a successful pgcy. But I don't think clotting issues were my problem. I did LIT, chiropractic, acupuncture, changed my diet to eat every 2 hours to stabilize my blood sugar, all of which was to help deactivate my over-active immune system. I threw everything but the kitchen sink at my infertility! I have no idea if any of it helped, though I think it did since all this cured my chronic urticaria which is a symptom of thyroid disease, another immune issue. Once I stopped all that it came back. We did PGD as well which was likely the #1 reason we were successful.
I am just popping in from the AP board but couldnt pass this by withouting adding my bit.
For those of you with recurrent mc and a negative for antiphopholid antibodies, I cant reccomend repeating the tests enough. I tested - and continued to mc and finally another specialist repeated the tests and i came up +.
I've since been diagnosed with lupus as well.
I have used clexane - a low molecular weight heparin which i think is about the same as lovenox for 2 pregnancies, both succesful.
Also some foods can reduce your risks of clotting, such as leeks and garlic. Hope this is of some help to someone, i only wish someone had told me earlier.
All the best.
Re: Possible Causes For Recurrent Loss
Hi. Here is this...
I have thyroid disease. This can cause miscarriage. Most common is early miscarriage, but it is also linked to later term miscarriage and stillborn.
Also, with my thyroid being treated properly, heparin treatments for clotting disorders, I am still having miscarriages, along with other symptoms. I spoke with my PCP today and we are starting to think I have Celiac's Disease. After researching, this is also linked to recurrent miscarriage. It is all new info for me, but if this is indeed how to stop miscarrying, I am ready and willing. I am still in the research process, but if you are having miscarriages, it is definitely worth looking into. It IS genetic, so if anyone in your family has been diagnosed, chances are you have it too. I'm going to have my daughters and son tested so that I could prevent any future medical problems for them. It could take years to show up.
Chronic Diseases and Miscarriage Risk
Re: Possible Causes For Recurrent Loss
I wanted to add one I discovered today, although rare, called Chronic histiocytic intervillositis
I will update with links later.
Re: Possible Causes For Recurrent Loss
Wanted to add Balanced Reciprocal Translocation to your list under genetic issues.
Reciprocal Translocation - What is a Reciprocal Translocation
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