Methotrexate

(Date of issue: April 2016. Version: 1)

This factsheet has been written for members of the public by the UK Teratology Information Service (UKTIS). UKTIS is a not-for-profit organisation funded by Public Health England on behalf of UK Health Departments. UKTIS has been providing scientific information to health care providers since 1983 on the effects that medicines, recreational drugs and chemicals may have on the developing baby during pregnancy.

What is it?

Methotrexate (Maxtrex®, Metoject®) is a medicine that is used at different doses to treat a number of conditions.

Lower doses (25-30mg or less a week) of methotrexate, given by injection or as tablets, are used in cancer chemotherapy and in the treatment of autoimmune diseases including Crohn’s disease, rheumatoid arthritis and psoriasis.

High doses (50mg or more) of methotrexate are sometimes given by injection to a pregnant woman to terminate a pregnancy, or to end an ectopic pregnancy (where the pregnancy develops in the fallopian tube instead of in the womb and can be life-threatening to the mother). Higher doses may also occasionally be used in cancer chemotherapy.

Is it safe to take methotrexate in pregnancy?

No. Methotrexate used in early pregnancy can cause miscarriage and/or serious birth defects in the baby. Birth defects have almost always been seen with use of high doses of methotrexate. However, it is not yet clear whether use of lower doses of methotrexate during pregnancy may also cause birth defects in the baby. For this reason, use of methotrexate is not recommended during pregnancy. Methotrexate can stay in the body for some time. Most doctors recommend that women stop treatment with methotrexate at least three months before attempting to conceive. Any woman who is taking methotrexate and planning a pregnancy in the future should therefore speak to her doctor to discuss the possibility of switching to a different medicine before stopping contraception. UK guidelines state that women who have been treated with methotrexate for an ectopic pregnancy or a pregnancy termination should also avoid conceiving a baby for three months afterwards.

What if I have already taken methotrexate during pregnancy?

If you are pregnant or think you may be pregnant and are taking methotrexate, you should speak to your doctor as a matter of urgency. He/she will then be able to advise you about what you need to do next. Not every baby exposed to methotrexate in the womb will have birth defects. The information below may be helpful to you and your doctor when considering how likely it is that your pregnancy has been affected by methotrexate.

Can taking methotrexate in pregnancy cause my baby to be born with birth defects?

A baby’s body and most internal organs are formed during the first 12 weeks of pregnancy. It is mainly during this time that some medicines are known to cause birth defects.

High dose methotrexate for pregnancy termination or to treat ectopic pregnancy
Exposure to high dose methotrexate in the womb usually results in miscarriage. However, in rare instances where the pregnancy continues, there is a risk of serious birth defects in the baby. These include defects of the skull and face, the ribs and spine, and the fingers and toes. Some affected babies also have heart defects. Most babies with birth defects caused by methotrexate appear to have been exposed to methotrexate between weeks four and eight of pregnancy (where week four is the week of the first missed period in women who have a regular 28 day cycle).  No large-scale studies of babies exposed to high dose methotrexate have been carried out and it is therefore not possible to say exactly what the chance is of a live-born baby who was exposed to high dose methotrexate in the womb being born with birth defects.

Low dose methotrexate for the treatment of autoimmune disease
Methotrexate is usually used at a maximum dose of 25mg a week to treat autoimmune disease. It is currently unclear whether exposure in the womb to these lower doses of methotrexate can cause birth defects in the baby. Two small studies do not suggest that babies exposed to low doses of methotrexate for the treatment of autoimmune disease are at increased risk of birth defects. In addition to these studies there are case reports in the scientific literature of around 60 babies born without birth defects following exposure in the womb to low doses of methotrexate. However, there are also a handful of case reports of babies who were exposed to low dose methotrexate in pregnancy and who have birth defects similar to those caused by high dose methotrexate. It is not known whether these birth defects were actually caused by methotrexate, as genetic mutations (spelling mistakes in a person’s genes) can cause similar birth defects and were not tested for in the affected babies. However, until more research is carried out, low dose methotrexate cannot be assumed to be safe. It is also possible that each woman’s personal risk of having a baby with birth defects as a result of low dose methotrexate treatment in pregnancy depends on a number of things such as other medicines she is taking, her underlying illness, and her (and her baby’s) genetic make-up.

Methotrexate for cancer chemotherapy
Methotrexate is used in cancer chemotherapy at various doses, usually in combination with other medicines. No large-scale studies of babies exposed to methotrexate during cancer chemotherapy have been carried out. There are case reports in the scientific literature of 19 women who were treated for cancer with methotrexate during early pregnancy: 18 of their babies were not malformed, while the 19th (who was exposed to quite a high dose of 80mg/week methotrexate) had severe malformations of the face and skull. It is unclear whether the baby’s birth defects were caused by methotrexate exposure. However, until more research is carried out, methotrexate use in cancer chemotherapy cannot be assumed to be safe in pregnancy at any dose.

Can taking methotrexate in pregnancy cause miscarriage?

At high doses (50mg or more), methotrexate is known to cause miscarriage and is used medically to induce pregnancy loss.

It is unclear whether lower doses (25-30mg or less) of methotrexate, as used in the treatment of autoimmune disease and in some types of chemotherapy, increase the risk of miscarriage. A single small study showed that miscarriage rates were approximately doubled in women taking methotrexate at doses of 30mg or less a week compared to rates in women with similar illnesses not taking methotrexate. However, a further small study found no link between methotrexate use and miscarriage. More research is therefore required to determine whether taking low dose methotrexate in pregnancy increases the risk of miscarriage.

No studies have assessed miscarriage rates in pregnant women exposed to methotrexate during cancer chemotherapy.

Can taking methotrexate in pregnancy cause stillbirth?

No studies have investigated whether use of methotrexate (at any dose) in pregnancy increases the risk of stillbirth.

Can taking methotrexate in pregnancy cause preterm birth?

It is unclear whether use of methotrexate in pregnancy (at any dose) increases the risk of preterm birth (before 37 weeks).

No studies have been carried out to determine whether exposure to high dose methotrexate or methotrexate used in cancer chemotherapy increases the risk of preterm birth. A single small study found no difference in the length of pregnancies between women taking low dose methotrexate for autoimmune disease and women with similar illnesses not taking methotrexate. However, more research into the possible effects of exposure to methotrexate at all doses on the risk of preterm birth needs to be carried out before conclusions can be drawn.

Can taking methotrexate in pregnancy cause my baby to be small at birth (low birth weight)?

Case reports in the scientific literature strongly suggest that babies with birth defects caused by exposure to high doses of methotrexate in pregnancy are also more likely grow poorly in the womb (‘intrauterine growth restriction’). There is also evidence to suggest that these children might continue to grow less well during childhood and even into adulthood.

A single small study found no difference in average birth weights of babies born to women taking low dose methotrexate for autoimmune disease and babies born to women with similar illnesses not taking methotrexate. However, more research into the possible effects of exposure to low doses of methotrexate and the risk of a baby being smaller than expected at birth needs to be carried out before conclusions can be drawn.

Can taking methotrexate in pregnancy cause learning and behavioural problems in the child?

A baby’s brain continues to develop right up until the end of pregnancy. It is therefore possible that taking certain medicines at any stage of pregnancy could have a lasting effect on a child’s learning or behaviour.

No large scientific studies have specifically investigated whether there is a link between using methotrexate in pregnancy and learning or behavioural problems (such as ADHD or autism spectrum disorder) in the child. There are, however, case reports of 31 people both with and without birth defects who were exposed to various doses of methotrexate in the womb. None were reported to have difficulties with learning or behaviour. There are also two case reports of children with birth defects caused by methotrexate, both of whom were developmentally delayed. However, in both cases other medical problems might have contributed to this. Large-scale studies into the effects of methotrexate exposure in the womb on a child’s learning and behaviour are required.

What are the risks to my baby if I become pregnant less than three months after stopping methotrexate?

Methotrexate can stay in the body for some time. Due to the possible (theoretical) risk that methotrexate left over in the body could affect a pregnancy, doctors recommend that women receiving treatment with methotrexate avoid becoming pregnant for three months after treatment has ended, and UK guidelines state that women should avoid pregnancy for three months following methotrexate treatment of an ectopic pregnancy.

In one small study, use of low dose methotrexate to treat autoimmune disease before pregnancy did not appear to increase the likelihood of miscarriage. However, the study did not provide any information on how long after stopping methotrexate treatment the women became pregnant. Another small study of women who had been treated with high dose methotrexate for ectopic pregnancy found that rates of miscarriage did not differ between women who conceived less than six months after treatment and women who conceived six months or more after treatment. In this study there was also no link between methotrexate use in the six months before pregnancy and the baby being born preterm or smaller than expected. There are also case reports in the scientific literature that describe 12 pregnancies that were conceived within six months of mothers receiving methotrexate treatment, mainly for autoimmune disease. All of the live-born babies were non-malformed, including a baby born to a woman who conceived two months after high dose methotrexate treatment for an ectopic pregnancy.

Although together these studies and case reports do not provide strong evidence that methotrexate exposure in the six months before a pregnancy is linked to adverse pregnancy outcomes, the way in which the information was collected, the small number of pregnancies studied, and the fact that none of the studies specifically assessed the effects of conceiving within three months of methotrexate treatment, mean that it is not possible to be certain that there is no risk of harm to a pregnancy. Additionally, almost all of the reported cases describe pregnant women receiving methotrexate treatment for autoimmune illness, where doses were likely to have been much lower than the doses used for termination of pregnancy or to treat ectopic pregnancy. Ideally, larger studies into the effects of conceiving within three months of methotrexate treatment (at all doses) are required.

Will my baby need extra monitoring during pregnancy?

If you have been exposed to methotrexate during the first trimester, or less than three months before pregnancy, and have decided to continue with your pregnancy, you may be offered more detailed anomaly scans from as early as around 12 weeks of pregnancy. It is, however, harder to see birth defects at this stage of pregnancy, which is why the main scan for birth defects is generally offered at around 20 weeks. It is important to understand that scans are not able to pick up all birth defects and cannot necessarily predict whether a baby will have problems with learning.

In general, women with some of the health problems that methotrexate is used to treat (such as cancer and autoimmune disease) will be more closely monitored during pregnancy to make sure that they remain well and that the baby is growing and developing as expected.

Are there any risks to my baby if the father has taken methotrexate?

Overall, there is no strong evidence of an increased risk to your baby if the father took methotrexate before or around the time you became pregnant. For more information please see the bump leaflet on paternal methotrexate exposure.

Who can I talk to if I have questions?

If you have any questions regarding the information in this leaflet please discuss them with your health care provider. They can access more detailed medical and scientific information from www.uktis.org.

General information 

Up to 1 out of every 5 pregnancies ends in a miscarriage, and 1 in 40 babies are born with a birth defect. These are referred to as the background population risks.  They describe the chance of these events happening for any pregnancy before taking factors such as the mother’s health during pregnancy, her lifestyle, medicines she takes and the genetic make up of her and the baby’s father into account.

Medicines use in pregnancy

Most medicines used by the mother will cross the placenta and reach the baby. Sometimes this may have beneficial effects for the baby.  There are, however, some medicines that can harm a baby’s normal development.  How a medicine affects a baby may depend on the stage of pregnancy when the medicine is taken. If you are on regular medication you should discuss these effects with your doctor/health care team before becoming pregnant.

If a new medicine is suggested for you during pregnancy, please ensure the doctor or health care professional treating you is aware of your pregnancy.

When deciding whether or not to use a medicine in pregnancy you need to weigh up how the medicine might improve your and/or your unborn baby’s health against any possible problems that the drug may cause. Our bumps leaflets are written to provide you with a summary of what is known about use of a specific medicine in pregnancy so that you can decide together with your health care provider what is best for you and your baby.   

Every pregnancy is unique. The decision to start, stop, continue or change a prescribed medicine before or during pregnancy should be made in consultation with your health care provider. It is very helpful if you can record all your medication taken in pregnancy in your hand held maternity records.

   

www.medicinesinpregnancy.org

Disclaimer: This information is not intended to replace the individual care and advice of your health care provider. New information is continually becoming available. Whilst every effort will be made to ensure that this information is accurate and up to date at the time of publication, we cannot cover every eventuality and the information providers cannot be held responsible for any adverse outcomes following decisions made on the basis of this information. We strongly advise that printouts should NOT be kept for any length of time, or for “future reference” as they can rapidly become out of date.

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