At CRGH, we adopt a personalized approach in the management of couples with recurrent miscarriage which includes new investigations like sperm DNA fragmentation testing, reproductive immunology, extensive evaluation of clotting disorders, genetics, endocrine testing and particularly we focus on the embryo-endometrium signaling pathway and offer treatment strategies to optimize pregnancy outcomes.
What is recurrent miscarriage?
A miscarriage is when you lose a pregnancy at some point in the first 23 weeks. When this happens three or more times it is called recurrent miscarriage.
Around one woman in every 100 has recurrent miscarriages. This is about three times more than you would expect to happen just by chance, so it seems that for some women there must be a specific reason for their losses. For others, however, no underlying problem can be identified; their repeated miscarriages may be due to chance alone. Most couples who have had recurrent miscarriages still have a good chance of a successful birth in future.
Why does it happen?
There are a number of causes which may play a part in recurrent miscarriage. It is a complicated problem and more research is still needed.
Your age and past pregnancies
The older you are the greater your risk of having a miscarriage.
For around three to five in every 100 women who have recurrent miscarriages, they or their partner have an abnormality on one of their chromosomes (the genetic structures within our cells that contain our DNA and the features we inherit from our parents). Although such abnormalities may cause no problem for you or your partner, they may sometimes cause problems if passed on to your baby.
Abnormalities in the embryo
An embryo is a fertilised egg. An abnormality in the embryo is the most common reason for single miscarriages. However, the more miscarriages you have, the less likely this is to be the cause of them.
Antibodies are substances produced in our blood in order to fight off infections. Around 15 in every 100 women who have had recurrent miscarriages have particular antibodies, called antiphospholipid antibodies (aPL), in their blood; fewer than two in every 100 women with normal pregnancies have aPL antibodies. Some people produce antibodies that react against the body’s own tissues; this is known as an autoimmune response and it is what happens to women who have aPL antibodies. If you have aPL antibodies and a history of recurrent miscarriage, your chances of a successful pregnancy may be only one in ten.
Another type of antibody that is associated with miscarriages is the antinuclear antibody. The disease that we typically associate with antinuclear antibodies is Systemic Lupus Erythematosus (SLE). The miscarriage rate in SLE patients is much higher than that of the general population. Although most women who suffer recurrent miscarriages do not have clinical signs of SLE, many exhibit autoimmune phenomena which is similar to that seen in SLE patients. The placentas in these women are inflamed and weakened.
Thyroid antibodies were markers for “at-risk” pregnancies. The two antibodies studied, anti-thyroid peroxidase and anti-thyroglobulin antibodies, are collectively referred to as anti-thyroid antibodies (ATA).
It is not clear how far major irregularities in the structure of your womb can affect the risk of recurrent miscarriages. Estimates of the number of women with recurrent miscarriage who also have these irregularities range from two out of 100 to as many as 37 out of 100. Women who have serious anatomical abnormalities and do not have treatment for them seem to be more likely to miscarry or give birth early. Minor variations in the structure of your womb do not cause miscarriages.
In some women the entrance of the womb (the cervix) opens too early in the pregnancy and causes a miscarriage in the third to sixth month. This is known as having a weak (or ‘incompetent’) cervix. It is overestimated as a cause of miscarriage because there is no really reliable test for it outside of pregnancy.
If a serious infection gets into your bloodstream it may lead to a miscarriage. If you get a vaginal infection called bacterial vaginosis early in your pregnancy, it may increase the risk of having a miscarriage around the fourth to sixth month or of giving birth early. It is not clear, though, whether infections cause recurrent miscarriage; for this to happen, the bacteria or virus would need to be able to survive in your system without causing enough symptoms to be noticed. This rules out illnesses like measles, herpes, listeria, toxoplasmosis and cytomegalovirus (so you do not need to be tested for them if you have recurrent miscarriages).
The Inherited Thrombophilias comprise a group of genetic disorders of the blood clotting pathways, leading to abnormal blood clot formation (thrombi). A common route involves resistance to a natural anticoagulant called activated protein C (APC). These diseases have been shown in several studies to cause vascular complications that lead to miscarriage, intrauterine fetal death, pre-eclampsia (toxemia of pregnancy), and the HELLP syndrome which is a severe form of pre-eclampsia characterized by hemolysis (blood cells breaking up), elevated levels of liver enzymes, and thrombocytopenia (a low platelet count).
Women who carry the genes for Inherited Thrombophilias are more likely (2 to 14 times) to have a clotting problem leading to a miscarriage, compared with the normal population. The three major gene mutations that lead to Inherited Thrombophilias are:
- Factor V Leiden mutation
- Factor II (Prothrombin) G20210 gene mutation
- Methylene-tetrahydrofolate reductase (MTHFR) mutation, leading to hyperhomocytseinemia
The most common cause of APC resistance arises from the point (one DNA based-pair) mutation at the cleavage site of factor V, called factor V Leiden. It is the most common of the Inherited Thrombophilias, with a prevalence of 10% in the Caucasian population. The mutation has been discovered in 60% of patients who have clot formation during pregnancy, and is also a major cause of blood clots associated with oral contraceptive use.
The Prothrombin (factor II) gene mutation has been shown to occur in 7.8% of women who experienced fetal loss due to a clotting disorder. Factor II is one of the major factors in the human clotting pathway.
Homocysteine is normally present in low levels in the bloodstream. It is derived from dietary methionine, an amino acid. A gene mutation for the enzyme methylene-tetrahydrofolate reductase (MTHFR), will lead to build up of homocysteine in the bloodstream. This condition, called hyperhomocytseinemia, results in blood clot formation and hardening of the arteries, even in childhood. Nutritional lack of vitamins B6, B12 and folic acid aggravate the problem. Women who have the homozygous form of the MTHFR gene mutation (both of her alleles having the mutation) are more than a two-fold increased risk for a miscarriage.
Recent studies have improved our understanding of the pathways that promote either the fertility permissive cells (Th2 and T regulatory) or the antagonistic cells (Th1, Th17 and Natural killer cells). Reducing abnormal pathways of immune activation and promoting those that encourage acceptance of the embryo/foetus may encourage the maintenance of the pregnancy from conception through to the delivery of a healthy baby.
If you have polycystic ovaries your ovaries are slightly larger than normal ovaries and produce more small follicles than normal. This may be linked to an imbalance of hormones. Just under half of women with recurrent early miscarriages have polycystic ovaries; this is about twice the number of women in the general population.
Having polycystic ovaries is not a direct cause of recurrent miscarriage and it does not mean that you are at any greater risk of further miscarriages. We are not sure what the link is.
Many women with polycystic ovaries and recurrent miscarriage have high levels of a hormone called luteinising hormone (LH) in their blood. Reducing the level of LH before pregnancy, however, does not improve your chances of a successful birth.
Diabetes and thyroid problems
Diabetes or thyroid disorders can be factors in single miscarriages. They do not cause recurrent miscarriage, as long as they are treated and kept under control.
What can be done?
Supportive antenatal care
Women who have supportive care from the beginning of a pregnancy have a better chance of a successful birth. There is some evidence that attending an early pregnancy clinic can reduce the risk of further miscarriages.
Screening for genetic problems
You and your partner should be offered a blood test to check for chromosome abnormalities; the test is known as karyotyping. If either or both of you turn out to have an abnormality you should be offered the chance to see a specialist called a clinical geneticist. They will tell you what your chances are for future pregnancies and will explain what your choices are. This is known as genetic counselling. It can help you decide what you want to do for the future.
If it seems likely that other members of your family could be affected by the same problem, they too may be offered genetic counselling.
Screening for abnormalities in the embryo
If you have a history of recurrent miscarriage and you lose your next baby, your doctors may suggest checking for abnormalities in the embryo or the placenta afterwards. They will do this by checking the chromosomes of the embryo through karyotyping, although it is not always possible to get a result. They may also examine the placenta through a microscope. The results of these tests may help them to identify and discuss with you your possible choices and treatment.
Treatment for aPL antibodies
There is some evidence that if you have aPL antibodies and a history of recurrent miscarriages, treatment with low-dose aspirin tablets and low-dose heparin injections in the early part of your pregnancy may improve your chances of a live birth up to about seven in ten (compared to around four in ten if you take aspirin alone and just one in ten if you have no treatment).
Even with treatment, you will have a risk of extra problems during pregnancy (including pre-eclampsia, restriction in the baby’s growth and premature birth). You should be carefully monitored so that you can be offered appropriate treatment for any problems that arise.
Steroids (certain sorts of natural or synthetic hormones) have been used to treat aPL antibodies in recurrent miscarriage, but they do not seem to improve the chances of a successful delivery and they carry significant risks for you and your baby, compared with aspirin and heparin.
Treatment for antinuclear antibodies
Women with ANA are treated with prednisolone, a corticosteroid, which suppresses the inflammatory process and stabilizes the cell. Prednisone does not pass through the placenta easily and is also broken down by enzymes in the placenta so that the fetus is exposed to only trace amounts. Additionally, the body produces the equivalent of 8 mg per day of this corticosteroid. When indicated, Prednisone should be started prior to conception.
Screening for abnormalities in the structure of your womb
You should be offered a pelvic ultrasound scan to check for and assess any abnormalities in the structure of your womb, so that they can be treated if necessary.
Tests and treatment for a weak cervix
If you have a weak cervix, a vaginal ultrasound scan during your pregnancy may indicate whether you are likely to miscarry.
If you have a weak cervix you may be offered an operation to put a stitch in your cervix, to make sure it stays closed. It is usually done through the vagina, but occasionally it may be done through a ‘bikini line’ cut in your abdomen, just above the line of the pubic hair.
Although having a cervical stitch after the third month of pregnancy slightly lowers your risk of giving birth early, it has not been proved to improve the chances of your baby surviving. Because all operations involve some risk, your doctors should only suggest it if you and your baby are likely to benefit. They should discuss the risks and benefits with you.
Screening for vaginal infection
If you have had miscarriages in the fourth to sixth month of pregnancy or if you have a history of going into labour prematurely, you may be offered tests (and treatment if necessary) for an infection known as bacterial vaginosis (BV).
If you have BV, treatment with antibiotics may help to reduce the risks of losing your baby or of premature birth. There is not enough evidence to be sure that it makes any difference to the chances of a baby surviving.
Treatment for thrombophilia
A combination of low-dose aspirin plus low molecular weight heparin injections is used to treat the inherited thrombophilias. The therapy starts before pregnancy occurs, and continued four to six weeks after birth. Folic acid supplementation is given to patients with the MTHFR gene mutation.
Test and treatment for immune system problem
Blood tests to look at NK cell count and activity may help reveal an underlying problem. Steroid therapy has been shown to reduce raised endometrial NK cells in women with recurrent miscarriage (American Journal of Reproductive Immunology 2010 AS Bansal).
It has been suggested that taking progesterone or human chorionic gonadotrophin hormones early in pregnancy could help prevent a miscarriage.
What could it mean for me in future?
Your doctors will not be able to tell you for sure what will happen if you become pregnant again. However, even if they have not found a definite reason for your miscarriages, you still have a good chance (three out of four) of a healthy birth.