Medical treatment with methotrexate
The term ‘medical management’, when used in relation to ectopic pregnancy, means using a drug called methotrexate.
What is methotrexate?
Methotrexate is a powerful drug which works by interfering, in a temporary way, with the processing in the body of an essential vitamin called folate. Folate is needed to help rapidly dividing cells – such as those of a pregnancy. The drug stops the pregnancy developing any further and the pregnancy is gradually reabsorbed. Methotrexate is also used to try and control other unwanted rapidly dividing cells, such as those which cause the condition rheumatoid arthritis, psoriasis, and some specialised cancerous lesions.
When is treatment with methotrexate most appropriate?
This method of treatment is more suitable for some women than others and is more likely to be successful in the following circumstances:
- You are in good health
- Your tube has not ruptured
- Your hCG level is low (your hospital will probably have a level above which this method will not be used)
- There is no signifiant abdominal bleeding.
Because it does not entail an operation, this method has an advantage over keyhole (or open) surgery if:
- You have other medical problems that may increase the risks of a general anaesthetic
- If you have adhesions in the abdomen or pelvis (as a result of previous surgery or infection)
- The ectopic pregnancy is situated in the neck of the womb or as the tube enters the womb.
Treatment of ectopic pregnancy with methotrexate is not appropriate if you suffer from any of the following conditions:
- An ongoing infection
- Severe anaemia or shortage of other blood cells
- Kidney problems
- Liver problems
- Active infection
- Peptic ulcer or ulcerative colitis.
How is the treatment given?
The treatment is given by means of an injection, usually given by a single injection into the muscle. However, if it needs to be administered by any other route, this will be discussed with you. The dose is calculated according to your height and weight. Before the injection, blood tests are done to check liver and kidney function and to ensure that you are not anaemic. Every 2-3 days, beta hCG levels will be monitored to ensure that they are falling appropriately. Most women only need one injection but in up to a quarter of cases a further injection may be required if serum hCG levels are not decreasing.
What happens after treatment?
This method has been developed to avoid surgery. However, it does require careful monitoring and follow-up. This means that you will have to attend the hospital regularly for blood tests until the tests are negative. This can take several weeks and this will be explained by your doctor. Your hospital will make arrangements for you to have the hormone level checked. Your doctors will usually test your hCG levels on the day the medicine is given, again on day 4, and on day 7 after the injections.
The hCG level often rises on day 4 and then your doctors are looking to see a drop in your hCG value of at least 15% between days 4 and 7. A few days after the injection, it is usual to begin to bleed and this bleeding can last between a few days and up to 6 weeks. It is usual to have some discomfort and pain initially but as long as this is not severe and you are feeling well this is nothing to worry about. If the pain persists for longer than 10 days, or is severe and is not helped by taking paracetamol, or you feel faint, you will need to go to hospital immediately as this may be a sign that the tube has ruptured.
What can I do to help the treatment work?
- You should stop taking any vitamins, minerals or other medicines unless you have been told by the doctors treating you to continue with them. Some medicines interfere with the effects of methotrexate. It is particularly important that you do not take any folic acid supplements until your doctors are sure that the medicine has worked
- You should not do any heavy lifting or housework until the hCG levels are dropping consistently and should only undertake gentle exercise, such as walking, until the hCG levels are below 100<mIU/mL
- You should avoid sexual intercourse until your levels are down to less than 100<mIU/mL
- Most people take time off from work initially and do not return to work for around 2 weeks while the treatment begins to work. Your hospital can give you a certificate to refrain from work for your employers or the Department of Social Security, so you can claim sickness benefit if you are entitled to it
- In the first week it is important to avoid pain killers which fall into the NSAID group such as ibuprofen. The preferred painkiller is paracetamol and you should refrain from drinking alcohol until the levels have fallen to a non-pregnant state.
What are the risks of being managed like this?
The main risk associated with treating you medically is that the medicine will not work and the cells of the ectopic pregnancy might continue to divide, which could result in there still being a need for surgery. Around 15% of women who are treated with methotrexate initially go on to need medical or surgical treatment. Doctors can tell if the specialised cells of a pregnancy that produce the hCG hormone are dividing because the hCG level will rise and not fall. Occasionally an ectopic pregnancy can rupture despite low hCG levels. If you are concerned about your level of pain, please contact your hospital.
What are the side effects?
Sometimes you may notice some mild to moderate abdominal pain. This tends to occur on day 3 or 4 after treatment. Many people feel very tired and are shocked by the sheer exhaustion that they encounter. Other occasional side effects (affecting up to 15% of patients) include nausea, indigestion, diarrhoea and sore mouth. Very occasionally, changes in the blood count, liver and kidney function may occur, but these are usually temporary.
How successful is it?
Success rates do vary depending on the circumstances in which methotrexate is given. Studies report success rates of 65-95%. Success rates tend to be higher with lower serum hCG levels. Your doctor should be able to tell you the success rate of methotrexate in their unit. Methotrexate is at least as good as surgery in terms of subsequent successful pregnancies. This may be due to the fact that medical treatment is non-invasive, whereas surgery may cause some scarring around the tube.
How will I know if there’s problem and I need a different treatment?
Your doctors will be able to tell if your pregnancy isn’t resolving, as this will be shown in the results of the regular blood tests. If this is the case, they will usually suggest surgery for you. A description of the signs of a deteriorating ectopic pregnancy, which include severely increased pain levels, vaginal bleeding, shortness of breath and pain in the tip of the shoulder, among others, which will alert you to the fact that you need to be reassessed, can be located here.
Your hospital should have given you a number to contact for health advice if you feel that anything is changing, or you will have been told to report to the accident and emergency department. If you have not been told what to do and need to speak to someone ring the hospital department which is treating you or NHS Direct on 111.
What precautions must I take for the future?
All women who suffer ectopic pregnancy are advised to avoid becoming pregnant for at least two proper period cycles, which is normally about three months. This is particularly important if you have been treated with methotrexate. This is because the methotrexate may have reduced the level of folate in your body which is needed to ensure a baby develops healthily. For example, it could result in a greater chance of the baby having a neural tube defect such as hare lip, cleft palate, or even spina bifida or other NT defects. The drug is metabolised quickly but can affect the quality of your cells, including those of your eggs and the quality of your blood for up to 3 or 4 months after it has been given. The medicine can also affect the way your liver works and so you need to give your body time to recover properly before a new pregnancy is considered. The current advice is to take folic acid for several months before you conceive. You must not begin to take folic acid supplements until the hCG levels have fallen to below 5<mIU/mL. Once your blood hCG levels have dropped, if you wish to become pregnant again, you should recommence your folic acid supplements several weeks or months before you conceive.
Until your doctors are confident that your pregnancy is ended it can be difficult to think about the future or for your emotions to surface properly. Being managed medically can be a worrying time for any woman, and until your hCG levels drop, you may still feel pregnant. Being worried about whether the pregnancy is resolving is quite normal and that is why your doctors are checking your hCG levels. However, women often say they feel guilty that they want the pregnancy to be over when they are also grieving for the loss of their baby. It is important you remember that the ectopic pregnancy was not your fault and that there was nothing you could have done to prevent it happening. More information about emotions is discussed here.
Frequently Asked Questions on Methotrexate
At what stage in pregnancy can I have methotrexate?
Methotrexate is most effective in the earlier stages of pregnancy, usually when the hCG level is below 3000. The risk of rupture is higher in pregnancies with levels greater than this. However, in cornual ectopic pregnancy it is not unusual to try to treat with higher levels. With ectopic pregnancy, it is not really the stage of pregnancy (as in the number of weeks gestation), but the size of the ectopic, which can vary over the first few weeks depending on the rate of growth, that is important. For a more detailed understanding of when Methotrexate might be considered, both this protocol and the Greentop Guideline 21 might be helpful. More information about methotrexate can be found on our message forums.
How long should I expect to bleed after Methotrexate?
The response of women to treatment with methotrexate varies greatly. The bleeding is from the lining of the womb and is hormonally controlled. It will probably last a week or two, changing in colour from red to brown and diminishing. As long as it is not too heavy, and is not associated with pain, you should not worry. Some women report bleeding and spotting for up to six weeks.
What happens when you have the shot of Methotrexate? Does the baby stay in the tube or does it get expelled? How will I feel?
In an ectopic, there is often a pregnancy sac, but most often a foetus or baby as we would know it, is not developing. What Methotrexate does is prevent the trophoblast cells from dividing. Trophoblast cells are the invading cells of the pregnancy and those that form the afterbirth or placenta. It is these that rupture the tube, cause the pain and have the potential to cause internal bleeding to the mother. Once these cells no longer divide, the pregnancy is ended and the whole pregnancy sac, including any cells that might eventually have grown into a baby, is usually reabsorbed by the mother. This is normal and happens in many cases of miscarriage. You may feel pain after being given methotrexate but this is due to the pregnancy sac swelling and not due to effects on the baby. The tube, however, may remain blocked by the pregnancy tissue which can take some time to shrink. Occasionally it may not shrink and will leave a blockage in the tube, by way of a small cyst. However, the use of Methotrexate does not reduce the chances of successful future pregnancy, whatever the outcome in the affected tube.
Women sometimes find treatment with Methotrexate quite a long and drawn out process. This can feel frustrating but the outcome is often very successful and it is worth persevering with the wait involved for the hCG levels to drop, and the repeated blood tests, until that happens.
My hospital will not offer Methotrexate, although I think I should be eligible for that treatment. What should I do?
The decision ultimately lies with your medical team within the health authority you are under, but there is never any harm in making it clear what your wishes are and asking to be assessed by someone who does use Methotrexate.
The use of methotrexate for treatment of ectopic across the UK is still varied. It may be that in one authority they use it, in the next they don’t. It’s as plain a fact as that and one that unfortunately does not help you. The use of methotrexate is still being researched so is not always available. If you would like it to be considered as a treatment, you certainly are within your rights to ask to be referred to a centre of treatment where it is available. You should ask to be referred to a consultant within the Primary Care Trust who can assess your suitability for this kind of treatment or on to another treatment centre.
If you need any help with this you need to contact PALS at the hospital where you are being treated. They can help you locate an assessment or new consultant if you need to.
Why does HCG level go up after a methotrexate shot?
The action of methotrexate is not instantaneous – it takes a few days for the cells of the pregnancy to stop dividing . It is the rapid division of these specialised trophoblast cells which causes hCG to be produced.
When we use methotrexate as a treatment for ectopic pregnancy, we expect to see a rise in the hCG level on day four after it has been given because we know the cells will have continued to divide for two or three days after it was given. More importantly we want to see a drop of at least 15% on day seven and if not, this is when the doctors will consider a second dose or surgery.
Is it normal to be exhausted after Methotrexate?
The way Methotrexate works is to deplete the body of the essential vitamin it needs to replicate cells. Our bodies are replicating cells all the time. The action of Methotrexate in the way that it is given to manage ectopic pregnancy medically is short-acting, but it is common for our bodies to be working very hard to recover from the depletion of folacin, which it is responsible for. On or around day 4 following treatment, it is very normal to feel utterly exhausted and this is because the drug interferes with essential amino acids that give us energy as a side effect.
You really do need to take things gently in the first couple of weeks after treatment with Methotrexate.
Folacin or folic acid in the form we take it in by our diets and supplements is a B vitamin and it is one of the vitamins that give us energy. It is important not to take folic acid supplements after treatment with Methotrexate until the doctors have confirmed that our hCG levels have fallen to 5<mIU/mL or below.
Feeling exhausted is a common complaint of Methotrexate treatment.
What happens to my baby when ectopic is treated with methotrexate?
WARNING – this is a difficult issue and may be painful to read. It should first be said that in ectopic pregnancy, because the egg has implanted in the wrong place, it is unable to source a good blood supply. As a result the ‘trophoblasts’ are trying to ‘burrow’ in to the walls of the structure the egg is stuck in and all energy and growth is occurring there. This means that our babies are not growing and so for more than 90% of us in ectopic pregnancy our babies do not, and have ever had, a heartbeat.
Methotrexate is a folate antagonist. This means it causes an essential substance needed to help trophoblast cells to divide to be released from the body. The cells can no longer divide because this essential substance is missing.
It is at this point the pregnancy tissue stops dividing. What then happens to this ‘tissue’ depends and varies with each woman.
The tissue can shrink and be reabsorbed by the body – this happens because it is our DNA and our cellular material in the first place and so the body just reuses its resources. However this ‘reabsorption’ can take weeks and sometimes months to be complete. Alternatively, it can appear to block the tube and over weeks, months or sometimes years ‘shrink’ to allow the tube some patency at a later date. The tissue can ‘sit there’ or cause a blockage, which may permanently block the tube. Or the tissue can separate from the tubal wall and be passed in the blood which is flowing out of the uterine cavity into the vagina.
Some women report what some doctors call separation pain, but many do not.
The bleeding that follows an ectopic pregnancy treated with methotrexate can be very heavy and clotty and result in the passing of what we call a decidual cast. This decidual cast can cause confusion, and the women can mistake it for the tissue of her baby. The lining of the uterus when we are pregnant, other than that which is taken up by the placenta, is called the decidua. The appearance of the normal lining of the uterus by the presence and action of progesterone becomes decidualised. When an area of the decidua is shed we call it a decidual cast. It is thought to occur as a result of the lack of stability of the integrity of the lining and this lack of stability is because the hormones aren’t functioning properly in an ectopic pregnancy. The sudden drop in hormones can cause the material inside the uterus to be shed in layers – the material that is passed can be grey, pink or white as well as appear like a clot or dark or frank red blood. It is very unlikely that if a woman passes material like this it is her baby, but she will often mistake it for that.
Is there anything I should avoid after methotrexate?
It is important is that anyone treated with Methotrexate avoids alcohol, NSAID drugs such as Ibuprofen and folic acid (this would include multivitamin complexes where there is a folic acid element) while the treatment is working.
What are the side effects of Methotrexate?
Here are the most common side effects:
- Abdominal pain. Cramping abdominal pain is the most common side effect, and it usually occurs during the first 2 to 3 days of treatment. Because abdominal pain is also a sign of a ruptured ectopic pregnancy, report any abdominal pain to your health professional.
- Vaginal bleeding or spotting.
- Nausea, vomiting, and indigestion.
- Fatigue, lightheadedness, or dizziness.
Rare side effects from methotrexate treatment for ectopic pregnancy include:
- Skin sensitivity to sunlight.
- Inflammation of the membrane covering the eye.
- Sore mouth and throat.
- Temporary hair loss.
- Severe low blood counts (bone marrow suppression).
- Inflammation of the lung (pneumonitis).
Why should I avoid alcohol after methotrexate?
The reason that drinking alcohol is advised against is because Methotrexate is metabolised in the liver in a similar way to alcohol. It is known to alter liver enzymes in the short term and traces of the drug can be found in the liver up to 100 days after the last dose. Therefore if the liver is very stretched through having to work too hard, it can cause you to feel very ill especially during the first couple of weeks after your treatment. It could also potentially damage your liver, so these are all good reasons to hold off.
When should I start taking Pre-natal vitamins after methotrexate?
If you have had either one or two injections of methotrexate you should wait until your hCG levels have fallen to below 5mIU/mL and then take a folic acid supplement for 12 weeks before you try to conceive.
This is because the methotrexate may have reduced the level of folate in your body which is needed to ensure a baby develops healthily. For example, it could result in a greater chance of the baby having a neural tube defect such as hare lip, cleft palate, or even spina bifida or other NT defects. The drug is metabolised quickly but can affect the quality of your cells, including those of your eggs and the quality of your blood for up to 3 or 4 months after it has been given. The medicine can also affect the way your liver works and so you need to give your body time to recover properly before a new pregnancy is considered. The current advice is to take folic acid for several months before you conceive. You must not begin to take folic acid supplements until the hCG levels have fallen to below 5<mIU/mL. Once your blood hCG levels have dropped, if you wish to become pregnant again, you should recommence your folic acid supplements several weeks or months before you conceive.
I haven’t bled following my treatment with methotrexate. What is wrong?
It is not uncommon for women who have been treated with methotrexate not to have any bleeding.
Is it safe to breastfeed following methotrexate?
The advice given to mothers who are taking regular oral doses of methotrexate, not for an ectopic pregnancy but to treat another entirely different condition, is NOT to breastfeed during their treatment.
Methotrexate is excreted into breast milk in low concentrations. The significance of this is not yet known. However, because the drug may accumulate in neonatal tissues, breast feeding is not recommended in long-term use of methotrexate. The American Academy of Paediatrics considers methotrexate to be contraindicated during breast feeding because of several potential problems, including immune suppression, neutropenia, adverse effects on growth, and carcinogenesis.
HOWEVER, the advice for women who have had Methotrexate for the treatment of ectopic pregnancy is different. In this case, Methotrexate is usually given as a one off dose (or occasionally two doses) by injection into a large muscle. It antagonises folic acid (vitamin B9) and causes it to be excreted, depleting the body of this essential vitamin.
If your baby is less than a year old and if breast milk is the sole source of nutrition, we advise avoiding breast feeding for at least four weeks following treatment with Methotrexate. If your child has been weaned, and is taking a balanced diet of mixed foods with an occasional breast feed for comfort, you may choose to start feeding again sooner than this.
In ectopic pregnancy, when one dose of methotrexate has been given, the risk is not the accumulation in neonatal tissues. The risk is that the milk will be of poor quality and of little nutritional use, due to the missing essential vitamins on which the body depends to support the division of rapidly dividing cells. This is very significant in small children as they are growing and relying on this crucial process.
To see our Frequently Asked Questions about recovery from ectopic pregnancy, please follow this link.