A Loss of Twins and Missed Opportunities for Cerclage

Recently, a reader left the comment below. The value and use of cervical cerclage continues to come into question. There are major institutions in this country where it is not considered to be a useful procedure and have abandoned or severely limited its use to selective patients in deference to ‘conservative management’, often now involving the administration of progesterone during the pregnancy. I have addressed my feelings on cerclage in a series published on this site many months ago (between August 18 and September 26, 2008). My feelings have not changed. There is a big difference between getting a couple of extra weeks to an extremely early pregnancy, or holding off delivery long enough to ‘get steroids on board’ for fetal lung maturation, and delivering a baby beyond 30 weeks gestation when the risk of long-term complications of prematurity are greatly diminished. Barely a week goes by on our service when a patient would have lost a pregnancy in the manner detailed below except for the timely recognition of cervical insufficiency and the placement of a cerclage in later midtrimester…

On June 10 Anonymous wrote:
I have read one of your previous articles regarding cervical cerclage. I was diagnosed with endometriosis, treated with laproscopy and subsequently underwent many IUIs and one cycle of IVF without success. My second IVF cycle was successful, but due to preterm premature rupture of membranes (PPROM) at 21 weeks, lost healthy twins. No history of diabetes or hypertension. Doctors could not diagnose the reason for PPROM, may be due to cervical incompetence. I was on total bed rest, but had some vaginal bleeding at 11 weeks. I just wanted to know if cervical incompetence could have been diagnosed before and cervical cerclage would have been useful. What are my chances of undergoing normal conception?

To anonymous June 10:
Conception and successful carriage of a pregnancy are separate issues. It sounds like you had (and may still have) cervical insufficiency with the twin pregnancy. I firmly believe that all multiple gestations, particularly those resulting in infertility patients, should be carefully evaluated for premature cervical changes by transvaginal ultrasound beginning as early as 16 weeks. If cervical changes were picked up early enough, a cerclage may well have been successful in preventing your pregnancy loss.

Twenty-five years ago, detecting and treating cervical incompetence in a 'first pregnancy' was rarely successful. The diagnosis of cervical incompetence (insufficiency) was a diagnosis of exclusion, usually after one or more premature deliveries or midtrimester pregnancy losses. But because of the increased surveillance by ultrasound, it is almost a weekly event on our service.

With a subsequent pregnancy, I would recommend serial cervical evaluation by ultrasound even if you have a single baby. You might also be a candidate for an elective/prophylactic cerclage at 13-14 weeks if you have any other risk factors such as a congenital uterine abnormality or previous cervical surgery (e.g., LEEP or conization). In addition, even if you and your providers decide only upon serial ultrasound evaluation, you might consider weekly injections with 17-OH-progesterone caproate beginning at 16-18 weeks as well. I am sorry for your loss, but with careful follow-up and pregnancy management, you should be successful in the future.
Kind regards,
Dr T

Labels: 17-hydroxyprogesterone caproate, 17P, cerclage, cervical incompetence, cervical insufficiency; premature labor

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Preterm Labor or Cervical Incompetence?: Unclear Diagnoses Complicate Choices for Therapy

Below are three comments from readers that appeared under my recent post on the safety of 17-hydroxyprogesterone caproate (17P) in the treatment of premature labor. They give us pause to reflect on the fact that the distinction between preterm labor and preterm labor and delvery secondary to cervical incompetence is often blurred, a fact that means selection of a therapeutic regimen is often not straightforward, sometimes delayed, and sometimes too late to improve the outcome in another pregnancy...

Thu Feb 07, 02:36:00 PM 2008 Anonymous said...

I have previously been pregnant 3 times and have delivered prematurely with all of them, 17 wks, 22 1/2 wks, and 7 1/2 wks. I am currently pregnant for the fourth time, and will be 16 wks this saturday. My doctors suggest that I have weekly injections of 17-hydroxyprogesterone to prevent preterm labor of this pregnancy, however, they are uncertain as to whether the cause is preterm labor or incompetent cervix. I am very skeptical when it comes to relying on drugs of any sort, and am not sure as to whether I should go through with this treatment or not, only to regret it later I have researched this and have not found enough inormation assuring its safety. I am currently on bed rest. Can strict bed rest keep me from delivering prematurely again, or will I need to have the injections administered? Are there any alternatives to this?

Thu Feb 14, 07:24:00 PM 2008 Kenneth F. Trofatter, Jr., MD, PhD said...

To Anonymous Feb 7: Personally, with your history, I would have placed the cerclage at 13-14 weeks, still followed your cervix with serial ultrasound examinations, starting at about 16 weeks, and considered the 17P if you had any evidence of uterine activity or cervical shortening. I think you would "regret" delivering early again much more than you will ever have cause for regretting the use of 17P. As an alternative, however, we have done a study with a vaginal progesterone compound (Prochieve) that seemed to be most effective in preventing early delivery in women with a short cervix (De Franco, et al., Ultrasound Obstet Gynecol 2007;30:697-705). Since this is a compound with the same 'natural' progesterone that your body and the placenta make, it should be completely safe for the baby. I do NOT trust bedrest alone under these circumstances for various reasons, especially if you have an incompetent cervix (and there are risks such as deep venous thrombosis and pulmonary emboli from prolonged bedrest). And I certainly do not trust progesterone alone in any form for a true incompetent cervix! Good luck and let us know how things turn out. Dr T

Thu Feb 07, 02:51:00 PM 2008 Anonymous said...

Dear Dr. T:

In your opinion, which is more beneficial, a cerclage or 17-hydroxyprogesterone injections? I was recently told What factors make me a candidate for either of these and determine their effectiveness? What are the risks and side-effects, long-term and short-term?

Thu Feb 14, 06:58:00 PM 2008 Kenneth F. Trofatter, Jr., MD, PhD said...

To Anonymous Feb 7: Your questions are straightforward and excellent and the answer is not so simple. At some point I will have to devote another whole post to cerclage. The answer depends on what your doctors think they might be treating and quite frankly, that depends, somehwat, on a detailed review of the previous pregnancy complications that have led you to this point. If you truly have an 'incompetent cervix', personally, I am a cerclage person. Placed early in pregnancy (13-14 weeks), a cerclage carries very low risks and is highly effective if the person who has placed it really does it right. Unfortunately, many cerclages are NOT well-placed and their efficacy has come into question more for this reason than anything else.

Your doctors probably have not been able to determine (based presumably on your past OB history) whether you had problems related to premature labor or whether you have an incompetent cervix. (It can be extremely difficult once the cervix has begun to change to decide which came first, the cervical change or the contractions). Under those circumstances, we will often follow you with cervical ultrasounds, consider using 17P if the history is strong enough, and then place a 'rescue cerclage' if and when the cervix starts to shorten (particularly if there is "funneling" of the membranes into the cervical canal), although this might not happen until 18-22 weeks (and sometimes even later). Of course, placing a cerclage at this point always carries more risk (primarily related to infection) than if placed earlier in the pregnancy, but again, in experienced hands, it is often successful in prolonging pregnancy, especially if very early preterm birth appears imminent if something isn't done (and there is no evidence of intrauterine infection already). The 17P appears to be relatively safe from midtrimester on, but I would suggest you read the blogs I have already posted on this subject. I wish you luck! Please let us know how things turn out.
Dr T

Fri Feb 08, 05:46:00 PM 2008 Anonymous said...

Dear Dr. Trofatter:

If I take 17P for one pregnancy, would I be required to take it for all future pregnancies, or will I be given the option?

Thu Feb 14, 07:29:00 PM 2008 Kenneth F. Trofatter, Jr., MD, PhD said...

To Anonymous Feb 8: If the 17P has a beneficial effect in your case, that will not carry over to another pregnancy. It has no long-term benefits. If you take it for one pregnancy, didn't really need it, and did well, you'll probably do well the next time whether or not you take it! The question is, do you want to take the chance of not taking it if you really do benefit it! Wish the answers were simple, but they are not! Thanks for reading!
Dr T

Labels: 17-hydroxyprogesterone caproate, 17P, cervical incompetence, preterm labor

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Is 17-Hydroxyprogesterone Caproate (17P) Safe for the Baby During Use in Preterm Birth Prevention?

Recently, I received the following two comments from readers regarding their concerns about the use of 17-hydroxyprogesterone caproate or 17P (formerly known as Delalutin) in the management of preterm labor. Their specific concerns are related to the possibility of congenital birth defects. My greater concern is that despite the fact both of them previously had preterm births, I am not sure either one of them has a really good reason to be placed on 17P, but we will save that discussion for another day!

•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?

Thanks

•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!

Labels: 17-hydroxyprogesterone caproate, 17P, delalutin., preterm delivery

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