Overview and expert assessment of off-label use of misoprostol in obstetrics and gynaecology: review and report by the Collège national des gynécologues obstétriciens français.

The literature suggests that misoprostol can be offered to patients for off-label use as it has reasonable efficacy, risk/benefit ratio, tolerance and patient satisfaction, according to the criteria for evidence-based medicine. Both the vaginal and sublingual routes are more effective than the oral route for first-trimester cervical dilatation. Vaginal misoprostol 800µg, repeated if necessary after 24 or 48h, is a possible alternative for management after early pregnancy failure. However, misoprostol has not been demonstrated to be useful for the evacuation of an incomplete miscarriage, except for cervical dilatation before vacuum aspiration. Oral mifepristone 200mg, followed 24-48h later by vaginal, sublingual or buccal misoprostol 800µg (followed 3-4h later, if necessary, by misoprostol 400µg) is a less efficacious but less aggressive alternative to vacuum aspiration for elective or medically-indicated first-trimester terminations; this alternative becomes increasingly less effective as gestational age increases. In the second trimester, vaginal misoprostol 800-2400µg in 24h, 24-48h after at least 200mg of mifepristone, is an alternative to surgery, sulprostone and gemeprost. Data for the third trimester are sparse. For women with an unripe cervix and an unscarred uterus, vaginal misoprostol 25µg every 3-6h is an alternative to prostaglandin E2 for cervical ripening at term for a live fetus. When oxytocin is unavailable, misoprostol can be used after delivery for prevention (sublingual misoprostol 600µg) and treatment (sublingual misoprostol 800µg) of postpartum haemorrhage. The use of misoprostol to promote cervical dilatation before diagnostic hysteroscopy or surgical procedures is beneficial for premenopausal women but not for postmenopausal women. Nonetheless, in view of the side effects of misoprostol, its use as a first-line treatment is not indicated, and it should be reserved for difficult cases. Misoprostol is not useful for placing or removing the types of intra-uterine devices used in Europe, regardless of parity.

[Misoprostol: off-label use in the treatment of post-partum hemorrhage]. / Misoprostol : utilisation hors AMM dans la prise en charge de l'hémorragie du post-partum.

INTRODUCTION: Current knowledge on off-label use of misoprostol for prevention and treatment of post-partum haemorrhage (PPH). MATERIALS AND METHODS: Systematic review of French and English literature by searching in PubMed, The Cochrane Library and recommendations of international scholarly societies and the World Health Organization. RESULTS: Oral misoprostol reduces the risk of severe PPH (≥1L) by more than 80% when compared to a placebo (P<0.02, RR 0.20 [0.04-0.91]), and reduces the risk of moderate PPH (500 mL) by almost 50% (P<0.0001, RR 0.53 [0.39-0.74]). These results are confirmed by numerous studies. On the other hand, compared to oxytocin, misoprostol is slightly less efficient in preventing PPH. Severe PPH is significantly more frequent in patients receiving misoprostol when compared to those receiving 10 IU of syntocinon intravenously or intramuscularly (RR 1.39 [1.19-1.63]). Use of misoprostol is associated with a higher risk of using other uterotonics (P<0.001). Regarding treatment of PPH, misoprostol (800 µg sublingual) could be an alternative to oxytocin (40 IU intravenous) when the later is not available. Active bleeding is equivalently stopped with misoprostol and with oxytocin (RR 1.12 [0.92-1.37]). However, more side effects are recorded with misoprostol, especially diarrhoea, nausea and vomiting but also tremors (RR 2.80 [2.25-3.49]) and fever above 38°C (RR 8.07 IC [5.52-11.8]). CONCLUSION: In prevention of PPH, a single dose of 600 µg of misoprostol sublingual (3 tablets of 200 µg) can be indicated during the third stage of labour, when oxytocin is not available. For treatment of PPH caused by uterine atony, a single dose of 800 µg of misoprostol sublingual (4 tablets of 200 µg) can be indicated if oxytocin is not an option. Combined use of misoprostol and oxytocin has not been proved to be more efficient.

Fragile sites are preferential targets for integrations of MLV vectors in gene therapy.

Following gene therapy of SCID-X1 using murine leukemia virus (MLV) derived vector, two patients developed leukemia owing to an activating vector integration near the LMO2 gene. We found that these integrations reside within FRA11E, a common fragile site known to correlate with chromosomal breakpoints in tumors. Further analysis showed that fragile sites attract a nonrandom number of MLV integrations, shedding light on its integration mechanism and risk-to-benefit ratio in gene therapy.