Anon

Is it safe to take methotrexate when trying for a baby?

Please can you provide me with more information regarding methotrexate and farthering a child? My husband is currently taking methotrexate and has been unable to come off the drug to have a family, however we have been reading new information on an Arthritis website saying this is no longer the case, and he can carry on taking the medication and try for a baby. Is this correct? And how did they come up with this information?

23 September 2019

Thank you for contacting Health at Hand.

We can truly sympathise with your predicament. We're glad that the methotrexate is working well. However, if you want to start having a family it can affect pregnancy so needs serious consideration. A man wishing to have children whilst they are taking methotrexate is a well-recognised issue. However, currently there are few studies focusing on this aspect and available data is limited because the number of men taking part in these few studies is relatively small.

What is methotrexate and how does it work?

Methotrexate (also referred to as MTX) is a medicine used in the treatment of a number of autoimmune conditions including rheumatoid arthritis, Crohn’s disease, ulcerative colitis, cancer and irritable bowel syndrome. It stops the action of an enzyme called dihydrofolate reductase. This enzyme is essential in making DNA and other natural processes in the body. It depletes folic acid from the body so it is usual to have a folic acid supplement on a weekly or twice weekly basis if you are taking methotrexate.

How does it affect fertility and the unborn child?

It depletes folic acid in the body so it is known to have harmful effects on unborn children. It does not appear to have effects on testicular function but it is known to affect sperm count probably because of its effect on the folate levels in the body. The folate levels can reduce the production of DNA.

Methotrexate is thought to be harmful when a woman takes it during pregnancy but there have been mixed results when the effects of methotrexate have been studied in humans.

Supporting (evidence based) studies

One study reported in a dermatology journal in 1980, in which methotrexate was used in the treatment of psoriasis, showed that the structure and the making of sperm were impaired but there was no effect on the levels of testosterone.1 Testosterone is a male hormone which amongst other functions is needed for the production of sperm.

Another study showed that there was no effect on the sperm or the baby.2

The Motherisk Programme, conducted at the University of Toronto in 2003 by French and Koren, reported that there have been ‘no reports of pregnancy outcomes among men exposed to methotrexate before conception’.3

In 2009 a team who were involved in the treatment of a man with methotrexate for Crohn’s disease, reported that a 41 year old man who was taking methotrexate and infliximab had a healthy baby who weighed 2.8Kg.4

In 2011 the Journal of Rheumatology reported a study that looked at the risk of major malformation in the case of fathers taking methotrexate at the time of conception. The dose of methotrexate ranged from 7.5mg-30mg taken once a week. Out of the 42 pregnancies involving 40 men who took part, 36 resulted in live births, 3 spontaneous abortions and 3 voluntary abortions. There were no congenital malformations observed at birth.

In 2014 a team led by Weber-Shendorfer followed 113 fathers whose partners had conceived while they were taking low dose methotrexate and compared the results to 412 fathers whose partners had also conceived but were not taking methotrexate. They found very little difference in the two groups, leading them to conclude that the risk of harmful effects on the babies born to fathers taking methotrexate was no greater than those who did not take methotrexate at the time of conception. They suggested that there is no need to postpone family planning if the father is taking low-dose methotrexate.5

In 2015 the British Society of Rheumatology produced a full guideline on the effects of drugs in pregnancy and lactation in a PDF format. The guideline reported that there were four groups, three case series and a case report that looked at 263 pregnancies where fathers were taking low dose methotrexate. The journal stated that:

‘Overall, the quality of these studies was low with information lacking from several studies primarily looking at safety of other medications. A large study however, published after our final search date of 113 pregnancies after paternal exposure to low dose methotrexate did not identify an increased risk of adverse fetal outcomes compared with 412 non-exposed pregnancies.'6

More recently,

Guidelines from the British Society of Rheumatology state that there is no need for men to stop methotrexate if they want to father a child. They stated that based on limited evidence, low dose methotrexate may be compatible with paternal exposure.

A 2017 study involving a very large (849,676 live births) cohort concluded that paternal exposure to methotrexate within 90 days before pregnancy was not associated with congenital malformations, stillbirths and preterm births.7

Older recommendations suggested stopping methotrexate 3 months before trying for a baby. This recommendation was based on how long sperm take to develop and not on actual evidence based experience.8

In October 2018, The American College of Rheumatology published an systematic review and meta-analysis on the subject of prospective fathers taking methotrexate. Twelve studies were identified assessing the congenital malformations following prospective father’s exposure to methotrexate of which 3 were case reports. Three studies included 265 fathers exposed to methotrexate and 1,004,834 were not exposed to the drug. Among the 265 fathers exposed, 13 had malformations of which 7 (2.64%) were major. Among the 1,004,834 fathers not exposed, 50,576 had malformations, of which 33,816 (3.37%) were major.

The authors concluded that from these data they found no association of fathers taking methotrexate prior to conception and all congenital malformations. They then concluded that there is no evidence supporting the current recommendations that men should discontinue taking methotrexate before conception.

Please note that just from this abstract it is not clear when the fathers in the study actually stopped taking methotrexate prior to conception, or indeed what dosage they were taking.9

In June 2019, the BMJ journals in the annals of Rheumatic Diseases published an abstract to include the same studies but with more detailed explanation of the studies included.10

In summary

The data available did not identify any increased risk of congenital malformation, growth restriction, spontaneous abortion or preterm delivery and other harmful effects to the baby.
The reports suggest that any harmful effects can be related to the dose.
Recent evidence there is no need for potential fathers to stop taking Methotrexate when trying for a baby.

I suggest that both of you discuss this matter thoroughly with your husband’s GP and rheumatologist. They may decide that your husband continues taking low dose methotrexate and while you try for a baby. If you become pregnant whilst your husband is taking methotrexate you will need more frequent detailed scans and monitoring will be required.

We hope this helps.

Answered by the Health at Hand pharmacists

References

1 Sussman A, Leonard JM. Psoriasis, methotrexate, and oligospermia. Arch Dermatol 1980; 116: 215–7.

2 Feagins LA, Kane SV. Sexual and reproductive issues for men with inflammatory bowel disease. Am J Gastroenterol 2009; 104: 768–73.

3 French AE, Koren G. Effect of methotrexate on male fertility. Can Fam Physician 2003; 49: 577–8.

4 Lamboglia F, D'Inca R, Oliva L, Bertomoro P, Sturniolo GC. Patient with Severe Crohn's Disease Became a Father While on Methotrexate and Infliximab Therapy. Inflamm Bowel Dis 2009; 15: 648–9

5 Weber-Schoendorfer C, Hoeltzenbein M, Wacker E, Meister R, Schaefer C. No evidence for an increased risk of adverse pregnancy outcome after paternal low-dose methotrexate: an observational cohort study. Rheumatology 2014; 53: 757–63.

6 Beghin D, Cournot MP, Vauzelle C, Elefant E. Paternal exposure to methotrexate and pregnancy outcomes. J Rheumatol. 2011;38(4):628–632.

7 Eck, L.K.; Jensen, T.B.; Mastrogiannis, D.; Torp-Pedersen, A.; Askaa, B.; Nielsen, T.K.; Poulsen, H.E.; Jimenez-Solem, E.; Andersen, J.T. Risk of Adverse Pregnancy Outcome After Paternal Exposure to Methotrexate Within 90 Days Before Pregnancy. Obstet. Gynecol. 2017, 129, 707–714.

8 Gutierrez, J.C.; Hwang, K. The toxicity of methotrexate in male fertility and paternal teratogenicity. Expert Opin. Drug Metab. Toxicol. 2017, 13, 51–58.

9 Jensen TB, Bring Christensen M, Trærup Andersen J. Paternal Use of Methotrexate (MTX) and Congenital Malformations – a Systematic Review and Meta-Analysis [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 10).

10 Bo Jensen T, Christensen MB, Tsao N, et al. THU0670 PATERNAL USE OF METHOTREXATE AND CONGENITAL MALFORMATIONS: A SYSTEMATIC REVIEW AND META-ANALYSIS. Annals of the Rheumatic Diseases 2019;78:631-632.

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