Systematic review on the safety of methotrexate in rheumatoid arthritis regarding the reproductive system (fertility, pregnancy, and breastfeeding).
OBJECTIVE
To analyze the safety of methotrexate (MTX) in rheumatoid arthritis (RA) regarding the reproductive system (fertility, pregnancy, and breastfeeding).


METHODS
Systematic review of studies retrieved by a sensitive search strategy in Medline (1961 - October 2007), Embase (1961 - October 2007), Cochrane Library (up to October 2007), and from the abstracts of the ACR (2005, 2006) and EULAR (2005 - 2007) annual scientific meetings.


METHODS
a) population: studies had to include patients with RA; b) intervention and control: discontinuation of MTX or elective abortion versus continuation of MTX or continuing pregnancy; and c) outcomes: infertility, oligospermia, reversibility, miscarriages, malformations, premature babies, healthy newborn, percent of the dose of MTX that passes to human milk, adverse effects in the lactating child. There was no limitation regarding study design, except for case reports, or language.


RESULTS
MTX and pregnancy: we selected 6 articles for detailed evaluation from 847 initial ones from the literature search. They were descriptions of cases obtained from searching retrospectively clinical databases of individual centers or from surveys. Patients had been exposed to MTX at doses used in rheumatology (5-25 mg/w), from conception to first trimester of pregnancy. Total number of MTX exposed pregnancies is 101, and the pooled outcomes (elective abortion not included): 19 miscarriages (23% of pregnancies); 55 live births (66% of pregnancies); and 5 of them had minor neonatal malformations (5% of pregnancies). The rate of induced abortions is 18%. MTX and lactation and fertility: no articles fulfilled the selection criteria. There is indirect evidence on the excretion of MTX in human milk and probably of reversible infertility from case reports.


CONCLUSIONS
This review exposes the shortage of data on the safety and risks of MTX during conception, pregnancy and lactation at the doses commonly used in rheumatology. MTX and pregnancy: there is not sufficient evidence to support whether it is MTX or the disease what underlies miscarriage in these patients. Pooling the data from the studies included, the rates of miscarriages and of birth defects are similar to the rates observed in healthy population. MTX and lactation and fertility: there is absence of confirming evidence.
Martínez Lopez
J A
JA
Research Unit, Fundación Española de Reumatología, Madrid, Spain. juan.martinez@ser.es
Loza
E
E
Carmona
L
L
D000328:Adult; D000818:Animals; D018501:Antirheumatic Agents / Q000009:adverse effects*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D016206:Databases, Bibliographic; D047108:Embryonic Development / Q000187:drug effects; D005260:Female; D005298:Fertility / Q000187:drug effects; D047109:Fetal Development / Q000187:drug effects; D006801:Humans; D007774:Lactation / Q000187:drug effects; D008297:Male; D018811:Maternal Exposure / Q000009:adverse effects*; D008727:Methotrexate / Q000009:adverse effects*; D011247:Pregnancy; D011256:Pregnancy Outcome; D012098:Reproduction / Q000187:drug effects*
D018501:Antirheumatic Agents; D008727:Methotrexate