Is 17-Hydroxyprogesterone Caproate (17P) Safe for the Baby During Use in Preterm Birth Prevention?
•At Wed Jan 02, 10:11:00 AM 2008, Anonymous said…
Hello- I'm currently 15 weeks pregnant with my 3rd child. I have six year old twins that were born at 34 weeks (I originally went into PTL at 29 weeks). With a few rounds of Mag Sulfate and bedrest and drugs at home I was able to hold off until 34 weeks for delivery. My OB is suggesting Delalutin at 16 weeks in an effort to avoid the possibility of preterm labor with the pregnancy. I'm concerned because there are so many horror stories on the web about limb deformitites and stillborn babies from delalutin. Most seem to be from the 70's - has the product changed much since then? Wouldn't it make sense to assume my previous pre-term issues were related to a twin pregnancy?
•At Wed Jan 09, 10:38:00 AM 2008, Anonymous said…
I too am in a similar situation. I gave birth to my son at 29 weeks due to a severe infection. My doctor also wants to put me on Delalutin injections starting at 17 weeks with my current pregnancy. I have researched this injection and found similar results to yours in terms of limb and genital defects as well as still births. I am extremely concerned and wondered in this medication has improved at all from the 70's as well. Any information would be greatly appreciated!
The use of 17P to help prevent early miscarriage and preterm birth dates back to the time before I started my residency in OB/GYN. In fact my first three children were 17P babies after my wife had had three consecutive miscarriages. Although there were no good controlled clinical trials, the teaching was that “It worked,” the side-effects for the mother were minimal (mostly injection site discomfort), and there did not appear to be the same level of risk for birth defects that was seen with DES. We went for a long period of time, however, when 17P was dropped from our regular armamentarium as we tried certain other drugs to help interrupt and delay preterm labor and birth. Unfortunately, none of these drugs have been very effective, almost all have unsatisfactory side-effects (and, in some situations, may be dangerous), and despite all efforts, the preterm birth rate has only continued to increase in the U.S. as we have addressed in this forum on previous occasions.
Although it is very difficult to predict who will have preterm labor and delivery, certain risk factors are associated with it and one of the most reliable is a prior history of preterm birth. Indeed, the earlier in gestation a prior preterm birth occurred, the greater the likelihood a woman will deliver prematurely again. And, if she has two or more preterm births, her risk can approach 50% that the next baby will be delivered early.
It was with cautious optimism then that we welcomed, a large, multicenter, randomized, double-blinded, placebo-controlled trial that showed weekly injections with 17P reduced by about one-third the risk of preterm delivery in women who had previously had a preterm birth (Meis, et al., N Engl J Med 2003;348:2379-85). That optimism grew when secondary analysis of the data revealed that 17P had its most beneficial effects on reduction of deliveries less than 34 weeks which incur the greatest risks for short- and long-term morbidity and mortality and excessive cost of medical care (Spong, et al., Am J Obstet Gynecol 2005;193:1127-31). In this later analysis, however, some concerns were also raised that there appeared to be a slightly higher fetal loss rate in the women who had received the 17P, but at this time, it cannot be concluded that this was the result of the drug itself or of other factors related to this high risk population of women. Early miscarriage rates and birth defects could not be commented upon in this study because the 17P was not begun until the patients were at least 16 weeks pregnant – well past the time of organogenesis and the usual time of miscarriage.
Anyway, returning to our readers’ comments, my first answer is no, the medication has not changed at all from the time it was introduced years ago. In fact, if anything, since the drug is now ‘formulated’ at compounding pharmacies across the nation, and is not under the scrutiny of BIG PHARMA (the product is no longer made by a pharmaceutical company – just wasn’t worth holding onto over the years), it’s composition is even less rigorously controlled, although the formulation is probably too simple to mess up in any way that would deleteriously affect either its safety or efficacy.
With regard to the issue of birth defects, especially the concerns related to limb and genital defects, let me first state that should probably not be a major worry at this point. As stated above, the currently recommended use of the drug involves starting it well beyond the development of the baby’s arms, legs, heart, genitalia, etc. All of that is basically completed by 12 weeks, and most even earlier. It is true that continued growth of all organs proceeds throughout the pregnancy and neurologic development, in particular, well beyond first trimester is especially important to the baby’s outcome, but to date, no data would suggest a major problem related to this. Of course, it will take many years to sort out whether or not subtle effects on the brain and neurologic or behavioral abnormalities are associated with the use of 17P.
To support these points, let me cite a few references. In 1982, Varma and Morsman evaluated the use of hydroxyprogesterone hexanoate (very similar to 17P) in early pregnancy for its adverse effects on fetal development (Int J Gynaecol Obstet 1982;20:13-17). One hundred and fifty women were begun on this drug by intramuscular injection at 6-8 weeks gestation and continued on therapy until 16-18 weeks. The control group consisted of 150 women with similar problems, primarily, recurrent miscarriages, who received no hormonal therapy. No significant differences related to adverse fetal/neonatal outcome or development were noted between the two groups.
The teratogenic effects of 17P have been evaluated in several animal studies. Seegmiller and colleagues (Teratology 1983;28:201-8) treated mice with doses of 17P ranging between 10 and 200 times the human therapeutic dose. At the highest doses (100 and 200 times the human doses), they found higher risks of maternal deaths (8% and 13%, respectively); and, all doses resulted in a slight increase in embryonic resorption (4-12% above controls). However, in surviving animals and their offspring, there were no significant affects on intrauterine growth, sex ratio, or malformation rates and it was specifically noted that the drug did not increase rate of masculinization, nor did it alter the development of nonreproductive organs.
In a later study, also done in mice, doses of 17P equivalent to 0.7, 7.0, and 70.0 times the dose in humans were administered between gestational days 7 through 19 – roughly equivalent to the period of most significant embryologic development in humans (Carbone and Brent, Am J Obstet Gynecol 1993;169:1292-8). In this study, no differences in fetal weight, resorptions, fetal deaths, number of male fetuses, or malformations were noted between the treated and untreated animals. Again, because of anecdotal concerns raised many years earlier, they specifically noted that there were no no increases in genital or nongenital birth defects, and no increase in limb deformities or bone calcification in the group treated with the 17P.
Hendrickx and colleagues (Teratology 1987;35:129-36) studied the effects of 17P given alone or with an estrogen (estradiol valerate) in rhesus and cynomolgous monkeys at weekly intervals between 20 and 140 days gestation. Although a higher rate of embryologic deaths were noted in the Rhesus monkeys (but not in the cynomolgous monkeys) at doses equivalent to (1X) and 10 times the human dose, no significant malformations or developmental abnormalities were identified. Not to belabor the work done to date in animal models, I would simply refer you to a recent review article on the subject by Christian and colleagues (J Matern Fetal Neonatal Med 2007;20:89-112). In this comprehensive review, the authors conclude that 3 studies point to a higher risk of embryo-fetal toxicity, including the ones cited above, but no consistent or significant teratogenic effect has been confirmed with the use of 17P.
Bringing this home, perhaps more reassuring is another recent study (Northen, et al., Obstet Gynecol 2007;110:865-72) that did follow-up evaluations of the babies born in the original 2003 17P trial of Meis and colleagues. At a mean age of follow-up in 194 children exposed to 17P and 84 placebo controls, “no significant differences were seen in health status or physical examination , including genital anomalies” between the 17P and the placebo children. Testing scores for “gender-specific roles” were also normal and comparable between the two groups. Since this is the only randomized, controlled study of substance published to date, it must be considered the most reliable information available as well and it would appear that 17P, as used in this trial, beginning at 16-18 weeks gestation, has a minimal risk for the fetus and newborn, at least from the standpoints of birth defects and development.
So, the final question...would I use 17P on my own kids again? Yeah, they all did turn out a little on the strange side, but look at who's their Daddy!