1 Atlanta Center for Reproductive Medicine, 100 Stone Forest Drive, Suite 100, Woodstock, Georgia, 30189, USA, 2 Reproductive Endocrinology and Infertility, Hopital de Nyon, 1260 Nyon, Switzerland, 3 Florida Institute of Reproductive Medicine, 836 Prudential Dr., Suite 902, Jacksonville, FL 32207 and 4 Jones Institute for Reproductive Medicine, 601 Colley Avenue, Norfolk, VA 23507, USA
Dear Sir,
In a recent paper, we reported our experience with vaginal administration of misoprostol (400 µg) at the time of intrauterine insemination (IUI) (Brown et al., 2001). The rationale for administrating misoprostol vaginally was to enhance uterine contractility and therefore, enhance transport of spermatozoa and in turn, IUI outcome. In this prospective trial, misoprostol was mixed into a 5ml inert triglyceride base suppository, primarily for the purpose of double blinding our placebo controlled prospective trial. The trial having been completed, several of us have opted for the clinical practice of placing 1 (D.D.Z.) or 2 (J.T.) 200 µg misoprostol (Cytotec) tablets in the vagina just after completing IUI.
We write to warn other clinicians that we have suspended clinical use of intravaginal Cytotec due to a much higher rate of both cramping and bleeding than had been observed in our randomized trial.
In the 25 cases using the 400 µg misoprostol dose (J.P.T.), 21 patients reported at least some cramping. The intensity ranged from mild (`like menstrual cramps') to very severe, with two patients presenting to the emergency room for pain management. The cramps lasted from an hour or two to as long as 3 days in a few cases. Furthermore, bleeding occurred in seven cases: five women had some spotting, and two others experienced full menstrual flow within 2 days of misoprostol application, suggesting complete luteolysis. Two of these 25 patients had chemical pregnancies; none were ongoing.
In 23 cases at the 200 µg dose (18 D.D.Z., 5 J.P.T), seven instances of serious cramping occurred. In two cases, severe cramps and menstrual like bleeding occurred as early as 1 h after application. In a total of three cases, cramping required emergency management of pain.
We suspect that these effects are due to different pharmacokinetics in the delivery of misoprostol in the study as compared with this clinical experience. In our randomized trial, two tablets of Cytotec 200 µg were broken up and then mixed into 5 ml of an inert triglyceride base. In the currently reported cases, the two Cytotec 200 µg tablets were simply placed in the posterior vaginal fornix. This may lead to a more rapid uptake of misoprostol and a higher incidence of adverse side effects.
Until the reason for this difference is explained and an appropriate adjustment is made, we are unable to recommend its use as described in this letter. We suggest there may be three alternatives for enhancing uterine contractility and thus, sperm transport and IUI outcome while minimizing these untoward side effects: (i) mixing Cytotec into a triglyceride base as was done in the original study; (ii) placing the supernatant of the sperm preparation in the vaginal fornix; and (iii) advising the couple to have intercourse soon after their IUI. Clearly, it would be beneficial to be able to provide these enhanced pregnancy rates if a suitable delivery system can be devised and experimentally verified.
Notes
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References
Brown, S.E., Toner, J.P., Schnorr, J.A. et al. (2001) Vaginal misoprostol enhances intrauterine insemination. Hum. Reprod., 16, 96101.