Recurrent pregnancy loss
Pregnancy loss and implantation failure are common fertility issues, but they can be particularly distressing for patients, when early hopes of a successful pregnancy are dashed. At CRGH, we adopt a personalised approach for women and couples experiencing recurrent pregnancy loss; understanding and compassion, coupled with leading edge investigations and support.
We have an established investigations service, including sperm DNA fragmentation testing, reproductive immunology, genetic testing, extensive evaluation of clotting disorders, endocrine testing, and a new range of tests focussing on endometrial health.
We have now introduced the UK’s first recurrent pregnancy loss clinic, combining a detailed medical assessment with ongoing support through early pregnancy.
Recurrent Pregnancy Loss Clinic
This new service is led by our expert in pregnancy loss, Dr Srividya Seshadri. The clinic is open to new and existing patients, and for patients trying to conceive naturally as well as those having fertility treatment.
You will have an initial consultation with a specialist nurse to take your history and carry out initial investigations. You will then consult with Dr Seshadri for a personalised management plan and medication if appropriate. You will then have regular telephone contact (2-3 times per week) with our specialist nursing team. Recent studies have demonstrated that intensive clinical and emotional support can have a significant positive impact on reducing pregnancy loss.
If pregnancy loss occurs again, your management plan will include methods to more accurately diagnose causes, adjust the management plan, and provide further support. Our specialist team will be with you every step of the way.
Dr Seshadri is an expert in pregnancy loss, with an international reputation, and an active research programme. Publications include:
- The role of immunotherapy in in vitro fertilization and recurrent pregnancy loss: a systematic review and meta-analysis https://www.fertstert.org/article/S0015-0282(18)30569-7/fulltext
- Natural killer cells in female infertility and recurrent pregnancy loss: a systematic review and meta-analysis https://academic.oup.com/humupd/article/20/3/429/728426?searchresult=1
What is Recurrent Pregnancy Loss?
A miscarriage or pregnancy loss is when you lose a pregnancy at some point in the first 23 weeks. When this happens two or more times it is called recurrent pregnancy loss. Around one woman in every 100 experiences recurrent pregnancy loss. This is about three times more than you would expect to happen just by chance, so it seems that for some women there are specific causes. For others, however, no underlying problem can be identified; their repeated pregnancy loss may be due to chance alone. Most couples who have had recurrent pregnancy loss still have a good chance of a successful birth in future, although the rate of pregnancy loss increases gradually with age
In around 5 in every 100 women who have experienced recurrent pregnancy loss, 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 pregnancy loss. CRGH can perform PGS testing on embryos prior to implantation to ensure genetically abnormal embryos are not transferred
Antibodies are substances produced in our blood in order to fight off infections. Around 15 in every 100 women who have had recurrent pregnancy loss 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 pregnancy loss, your chances of a successful pregnancy may be only one in ten.
Another type of antibody that is associated with pregnancy loss is the antinuclear antibody. The disease that we typically associate with antinuclear antibodies is Systemic Lupus Erythematosus (SLE). The pregnancy loss rate in SLE patients is much higher than that of the general population. Although most women who suffer recurrent pregnancy loss 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 pregnancy loss. Estimates of the number of women with recurrent pregnancy loss 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 pregnancy loss.
In some women the entrance of the womb (the cervix) opens too early in the pregnancy and causes a pregnancy loss in the third to sixth month. This is known as having a weak (or ‘incompetent’) cervix. It is overestimated as a cause of pregnancy loss 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 pregnancy loss. If you get a vaginal infection called bacterial vaginosis early in your pregnancy, it may increase the risk of having a pregnancy loss around the fourth to sixth month or of giving birth early. It is not clear, though, whether infections cause recurrent pregnancy loss; 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 pregnancy loss).
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 pregnancy loss, intrauterine fetal death, pre-eclampsia (toxemia of pregnancy), and the HELLP syndrome which is a severe form of pre-eclampsia characterised 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 pregnancy loss, 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 pregnancy loss.
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 pregnancy loss 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 pregnancy loss and it does not mean that you are at any greater risk of further pregnancy loss. We are not sure what the link is.
Many women with polycystic ovaries and recurrent pregnancy loss 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 pregnancy loss. They do not cause recurrent pregnancy loss, as long as they are treated and kept under control.
What can be done?
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.
See our section on Genetic Services for more information
Screening for abnormalities in the embryo
If you have a history of recurrent pregnancy loss 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 pregnancy loss, 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 pregnancy loss, 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 stabilises 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 pregnancy loss 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 continues 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 pregnancy loss (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 pregnancy loss.
If you would like to book an appointment with one of our doctors you can: