Evidence Based Use of Misoprostol in Second Trimester Induction
I was recently on call and we had 2 patients on our board having second trimester inductions, one for ruptured membranes at 17 weeks and another for fetal anomaly. Both patients were being treated with what seemed like a strange regimen of misoprostol, 400 mcg miso vaginally _and_ 400 mcg orally, every 4 hours. I had never heard of this regimen, and was wondering where it came from. None of the residents seemed to know, only that it had been passed down through some route to them.
It struck me as odd that people are using misoprostol in all kinds of different ways, despite the large amount of available evidence in the literature. In fact, it may be one of the most thoroughly studied topics in obstetrics, having been the subject of many randomized trials, a standard of research rarely achieved in our field. Studies have included both pharmacokinetic and clinical data. For better or for worse, abortion is the single most common procedure performed for women worldwide, and the patient population tends to be appreciative and willing to participate in research. Sadly, the mammoth amount of data available seems overlooked by the majority of practicing obstetricians, given the wide variation in practice I have observed. As such, I want to review a few of the major articles here.
I. A little pharmacokinetics
Misoprostol can be absorbed by many routes, and has different pharmacokinetic properties in each route. Miso is absorbed the fastest via sublingual route. Orally is slower than sublingual, but faster than vaginal/rectal routes. The vaginal or rectal route leads to a lower peak level of MPA (misoprostol acid), but has a much slower elimination curve. (Zieman et al.) There is some suggestion that repeated doses of vaginal miso may be inferior to repeated buccal/sublingual doses due to vaginal bleeding and subsequent degradation of vaginal absorption. These patterns are described in the following graph from Tang et al.
Graph from Tang et al Int J Gynaecol Obstet. 2007 Dec;99 Suppl 2:S160-7. Epub 2007 Oct 26.
This information is important because it effects the side effect profile and speed of onset of the drug. Oral or sublingual adminstration leads to higher levels and onset of action, but will be associated with greater side effect (predominantly fever and chills.)
II. Optimal dosing for second trimester induction
There have been a number of randomized studies investigating the optimal dosage of misoprostol for second trimester induction.
2003 Dickinson et al – randomized 150 patients undergoing second trimester abortion or induction of IUFD to 200 mcg Q6H, 400 mcg Q6H, and 600mcg then 200 mcg q6H, all delivered vaginally.
She found that 1) IUFD inductions complete much quicker than live abortions, and 2) 400 mcg q6H vaginally was the optimal studied dose, providing nearly the best delivery characteristics but avoiding the side effects associated with higher dosing.
(Graph adapted from Dickinson et al, reference below)
Newer research has investigated the use of sublingual miso for second trimester induction. Based on the pharmacokinetic data, we would expect this to lead to faster delivery but with higher side effects, as it achieves higher blood levels than the vaginal miso used in the Dickinson trial, but the data has not borne this out.
Tang et al did a randomized trial which showed vaginal misoprostol to be more effective than sublingual in second trimester induction.
“There was no significant difference in the success rate at 48 hours (sublingual: 91%; vaginal: 95%). However, the success rate at 24 hours was significantly higher in the vaginal group (85%) compared with the sublingual group (64%). There was no difference in the median induction-to-abortion interval (sublingual: 13.8 hours; vaginal: 12.0 hours). Significantly more women in the sublingual group preferred the route to which they were assigned when compared with the vaginal group. The incidence of fever was also less in the sublingual group.”
This is a little surprising, but may have to do with a downregulation of prostaglandin receptors associated with the rapid ascent of blood levels with sublingual miso.
Based on these data, the most evidence based dose of miso for second trimester induction is 400 mcg q6h vaginally.
Sources:
Academic OB/GYN 
Good info!
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Thanks!
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I would do a D and E. Safe, and likely easier for the patient. And don’t forget this is also a prefered route if prior uterine incision. But agree with the discussion, in general!
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I completely agree with you on this point. I also am comfortable with D and Es, but unfortunately we are in the minority of docs I think. The only docs that are good at 2nd Tri D and Es are the few that are doing abortions and some MFMs, and that’s the minority of people I think.
“And don’t forget this is also a preferred route if prior uterine incision.”
Lets get a source on that one. With a single uterine incision the rupture rate is about 0.4% (0 in some large series), while complication rates for D and E are above that even in skilled hands. Rates of perforation probably go up with prior scars as well. There’s also the issue of the mother wanting to see the fetus intact. I’m comfortable going either way, as should be most people.
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Based on these data, the most evidence based dose of miso for second trimester induction is 400 mcg q6h vaginally.
Times how many doses? Have you seen http://misoprostol.org/File/guidelines.php ? Good stuff.
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Until delivery.
That is a really great site, thanks for pointing it out. I’m going to tweet that out.
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I understand that you are using this for abortive purposes, but it was my understanding that this medication was not approved for use on pregnant women either by the FDA or the manufacturer. Is it problematic to use it in this context as well?
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Off label use of drugs in pregnancy is common. FDA approval in pregnancy is the exception, not the rule. People who have no real understanding of pharmacology and medicine love to point out that misoprotostol is not FDA approved in pregnancy, which is an utterly meaningless distinction. Drugs are used off label throughout medicine all the time, in and out of pregnancy.
The manufacturer (Searle) has no incentive to seek FDA approval, as the drug is not expensive and does not offer great profit, and is used anyway despite lack of such an approval. Another company has been trying to create a misoprostol insert that would pass FDA. If it does, it will cost hundreds of dollars instead of the pennies that generic cytotec costs, without any improvement.
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What are the reasons for 2nd trimester inductions/abortions? This topic always troubles me and I want to have accurate information that might inform my emotions. It might not be possible, but I am curious more than judgmental, accusatory, or have some platform to promulgate. On the face of it, these procedures don’t seem happy in any way and potentially very risky for the mother’s health. Please, correct me if I’m wrong.
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Second trimester inductions are done for a number of reasons. 1) a fetus that is anomalous to the point that it will not live, or has already died, leading to a need to bring the pregnancy to an end. 2) a mother who has a pregnancy complication that is threatening her life, such as early severe pre-eclampsia 3) a mother who is fundamentally sick to the point that the continuation of the pregnancy threatens her life, such as kidney failure or heart failure 4) a mother who has cancer and needs to end a pregnancy to take prompt treatment, 5) a pregnancy that is ending naturally, but will not finish without help, such as premature rupture of membranes prior to fetal viability, and yes 6) a mother that just wants an abortion (though most of these women have surgical abortions rather than inductions)
As for the risk, its extremely low. Its a vaginal delivery of a very small fetus/infant, which is not a particularly dangerous event.
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