Academic OB/GYN Podcast Episode 17 – Suture Physics

Usually the emotion after a web service stops working is furious anger.  How could you do this to me you stupid site!

But not Twitter.   The Fail Whale is so calming I am almost glad when the site is down.  He looks so happy to be out of the water.  He’ll be back in soon enough firing our tweets around, but for now he’s just flying around.    How can you get mad about that?

This is an example of brilliant web design.   When the site fails, you actually enjoy it and it makes you feel peaceful.  More sites should be like this.   That is all.

Here’s the message I am getting from a lot of folks strongly in favor of VBAC rights and availability.

The choice to VBAC is an informed refusal of a intervention.  There should be no “right” required to have it.  Hospitals should not be allowed to refuse VBAC attempts, as this is the same as requiring a woman to have an elective surgery.

I hear a general feeling that the risk of uterine rupture is overstated, as is the likelihood of a severe adverse outcome if a rupture occurs.

I hear a general feeling that the short and long term risks of repeat cesarean deliveries are overstated.

I think these are good messages.  I agree with women should be be free to refuse repeat cesarean delivery, even in hospitals that do not have 24 hour anesthesia access and 24 hour OB coverage.  As long as this refusal is informed, it should be a woman’s right.  I also agree that the risks of VBAC are overstated by many, and the risks of repeat cesarean are understated by many.

The problem is liability.

Hospitals where uterine ruptures have occurred have been hit with massive lawsuits, many of which were successful.  Obstetricians have also been successful sued for uterine ruptures, leading to massive settlements or judgements.  This has led hospital and physician medical liability carriers to increase rates substantially to hospitals and doctors who attend/provide VBACs, and in some cases refuse to insure them entirely.  In many cases this has made it financially difficult to make VBACs available.

So we can all argue that there is no such thing as “making a VBAC available”, as it is the natural state of affairs in a woman with a prior cesarean.   After all, if you do nothing she will go into labor and likely will VBAC.   This is a very logical and rational argument.  The problem is that liability is not rational.  Its based predominantly on completely irrational ideas that every bad outcome is somebody’s fault and that compensation must somehow be made.

The discussion at NIH is very rational, as are most of the arguments being made for VBAC availability.  The problem is that our history of lawsuits for uterine ruptures is completely irrational, as is the current situation with liability insurers.  The sad but simple reality is that many doctors and hospitals can’t provide VBAC because their liability carriers refuse to cover them if they do them, and without liability coverage medicine cannot be practiced in this country.  This is irrational, but it is real.
On one side we have lots of very rational arguments we can all get around, and on the other we have a completely irrational but very real issue that is the actual cause of the problem.

And so, I present a viable solution.

I propose a nationally accepted consent form for VBAC and repeat cesarean delivery, vetted by as many people as would want to be involved.  This VBAC consent form would discuss the true risks of VBAC to the mother and fetus, and the true risks of repeat cesarean delivery.  It would also discuss what we would consider to be adequate hospital coverage system to ensure optimal action in case of a uterine rupture, and whether or not the proposed delivery environment is able to meet those standards.  It would explain that not meeting these standards may decrease the efficiency of a response to a uterine  rupture.  It does not require that these standards are met, but does explain that failing to meet this standards may, in rare cases, contribute to an adverse outcome.  It will also explain that even if these standards are met, no guarantees can be made about outcome, that uterine rupture is an unpredictable event, and that uterine rupture can lead to injury or death, fetal or maternal.

Most importantly, this consent form would be a federal document, and would include a statement something like this:

“I understand that by signing this consent form I release any healthcare entity from any liability regarding a uterine rupture, if such an event occurred.  I understand that this is completely irrevocable in this pregnancy if I continue to choose vaginal delivery.  I sign this of my own free will.  I understand that I can choose an elective repeat cesarean at any time”

Such a release would require a federal law that made the release bulletproof, as normally people cannot completely release any entity from liability.  Such a law would probably be called unconstitutional by somebody, so that would have to be fought off. There is precent for such a law.  Vaccine manufacturers are federally protected from lawsuits from adverse outcomes from vaccines, under a law that created a separate liability pool for that specific issue.

Here are the steps that would be required.

1. Draft a consent form based on the best available evidence
2. Open the consent form to comments, and make edits as necessary
3. Draft a bill that would release parties from liability when this consent form is signed.
4. Gain interest of a few senators that would be interested in bringing this bill to the floor.
5. Raise up enough public support for this to actually make it law.
6. Fight off the constitutional battles that would ensue.

I believe that if such a thing could become law, VBAC availability would no longer be a problem.  Without the risk of a career destroying or hospital injuring lawsuits in the rare case of uterine rupture, there would be no reason to limit VBAC access.  The problem would be solved.

A lot of folks I have had discussions with are saying that that women understand the risks of VBAC and are willing to take that very small risk of uterine rupture and potential fetal harm.   The question then is, understanding the current liability situation, would they would be willing to sign away their right to sue in the event of a uterine rupture?  Figuratively, would they put their money where there mouth is?  Clearly this strategy would lead to hospitals refusing VBACs unless the federal consent were signed, and would put an end to uterine rupture lawsuits in general.

There are a number of barriers to generalized tort reform.  The biggest is the huge lobbying power of trial attorneys, and the sad fact that most of my political party is lawyers.  Perhaps what we need is specific issues we can draw attention to, like VBAC.  Perhaps we can have “micro tort reform” on this one issue.

I await public comment on this idea.  It would be a huge undertaking, but I think it would work.

Academic OB/GYN Podcast Episode 16 – Grey Journal February 2010

For my colleagues that haven’t had the opportunity to do one of these procedures, I want to lay out how its done.  In short, the goal is to place a cerclage between the ascending and descending branches of the uterine arteries, at the connection of the lower uterine segment and internal cervical os.  When you’re done it should look something like this -

So here’s how to do it

1 – start with a woman with an indication.  Several previous second trimester losses with at least one failed transvaginal cerclage.

2 – Create a transverse incision with Pfanenstiel fascial entry.

3 – Place a retractor.  In this case we used an O’Connor O’Sullivan, but a Balfour will also work.  An Alexis retractor may not work as well as it is harder to get behind the uterus without the upper blade holding back the bowel and fascia.  In a non-pregnant uterus is easier because you can be more aggressive about moving around the uterus for access.

4 – In a pregnant uterus, be careful with it.  Try not to compress the fundus, as one is potentially pushing the pregnancy down through a presumed incompetent cervix.  A spongestick pushing _up_ on the lower uterine segment is a good way to get exposure.

5 – Open the vesicouterine reflection and start making a bladder flap.  In a pregnant uterus this will bleed more than in a non-pregnant hysterectomy.  Hemoclips are useful for occluding the thicker vessels prior to transecting them.  Use blunt dissection with a peanut / Kirschner.

6 – Reach behind the uterus and feel behind the cervix.  Massage the posterior peritoneum laterally at the level of the internal os, pushing the uterine arteries laterally.

7 – Identify the uterine artery on one side visually, noting the bifurcation of the ascending and desceding branches.  Identify a free space between the bifurcation and the cervix.

8 – Note the ureter lateral to the interal os.  When you put the uterus on stretch the ureter will be just lateral to the birfurcation, running under the uterine artery.  With adequate stretch the ureter will pop up through the peritoneum and be very visible / palpable.   If you can’t see it you can strum it on the lateral sidewall lateral to the uterine artery bifurcation – it will pop like a guitar string.

9 – Put a 5 mm mersilene tape between the jaws of a right angle retractor.  Reach the right angle behind the cervix and then along the cervix lateral to the free space you identified.   Wiggle the right angle up through the peritoneum until you can cut through the peritoneum above it.  Grab the mersilene with a snap and carefully pull the right angle back. All pressure should be in pulling the tape _medially_ as lateral pressure will drag the mersilene against the uterine artery, which is to be avoided.

10 – At this point you may have bleeding from the hole you just made.  Slowly bring the mersilene up and hold it with pressure against the cervix, which should slow the bleeding as long as its venous.

11 – Repeat on the other side.

12 – Tie the mersilene anteriorly with 6+ knots. Sew the ends together with a small prolene or silk, and then cut the ends off.

13 – If pregnant, confirm that the pregnancy is still viable.

14 – Close.  As the patient will be having a cesarean in the near future, placement of a antiadhesion barrier is worth considering. I use SepraFilm for this.

Here’s another photo with the uterine arteries marked:

This procedure can also be performed laparoscopically both in and out of pregnancy, as described in several recent articles.

This study was based on data abstraction from 187 patients who were treated with single dose MTX for ectopic pregnancies, with demographics and HCG levels recorded over time.   Based on these data, a comparison was made between a Day 1,4,7 strategy and a Day 1,7 strategy.  Here’s what they found.

A Day 1,7 strategy has a very high sensitivity for picking up women who need another dose of MTX to successfully end an ectopic pregnancy, but a much lower specificity.  This means that with a Day 1,7 strategy many more women will get treated with a second dose of MTX than with a Day 1,4,7 strategy.  However, in tradeoff they will not need to get a day 4 blood draw.  Depending on Beta HCG levels, anywhere from 2 to 10 additional women will get a second MTX dose per Day 4 blood draw avoided with this strategy.

So here’s a few thoughts on this:

1) This strategy leads to a lot more methotrexate use, in order to avoid a blood draw.  From a cost point of view this could be a problem. Dr Thurman points out that MTX is inexpensive, but in many hospitals it is delivered as a chemotherapy agent.  Even if it is  regular injection, it usually isn’t available in the MD office and hospital nursing charges are high.  Actual cost of drug is low, but delivery of drug can be expensive.

2) Some people think we should be doing 2 dose MTX for everybody anyway.  Failure rates for single dose MTX are around 10% in a mixed population (2), though a mandatory 2-dose regimen hasn’t done much better in trials(3).   This regimen would be a middle ground between a 1 dose and mandatory 2 dose regimen.

As this is just pilot data, it will be interesting to see this against a 1,4,7 regimen in a randomized trial.  I know several of the investigators, and suspect that they will be doing this in the future.  I look forward to those results.   For now I will still use a 1,4,7 regiment, as to me a day 4 lab draw is not as big a deal as a second dose of MTX.  But that being said, if a patient really hated getting blood drawn, this might be a better option for them.   Then again if they hate blood draws much, maybe a laparoscopy would be better!

Source:

Thurman AR, Cornelius M, Korte J, Fylstra D. An alternative monitoring protocol for single-dose methotrexate therapy in ectopic pregnancy. Am J Obset Gynecol 2010; 202:139.e-16

Lipscomb GH, Bran D, McCord ML, Portera C, Ling FW. An analysis of 315 ectopic pregnancies treated with single-dose methotrexate. Am J Obstet Gynecol 1998;178:1354-1358

Barnhart K, Hummel AC, Sammel MD, Menon S, Jain J, Chakhtoura N
Use of “2-dose” regimen of methotrexate to treat ectopic pregnancy.
Fertil Steril. 2007 Feb;87(2):250-6. Epub 2006 Nov 13.

As an academic gynecologic surgeon, I often get asked a question that reminds of me of my calculus realization, and that question is “Who will be doing my surgery?”

Patients at a teaching center who are going to be having surgery often ask this question, wanting to make sure that the attending physician will be doing their surgery and not a resident or other trainee.  The answer that works the best is that we operate together, and that the attending is involved in every step of the way.  This sometimes works, but sometimes people don’t like that answer.  Often they ask “but who will be actually holding the knife?”

The truth is that in teaching centers, residents do most of the physical work of surgery, and typically it is they who are holding the knife.  Though attendings are involved and are usually scrubbed into the case, residents usually do most of the physical work.   Residents don’t do things they are not yet ready to do, but once they have amassed enough experience and knowledge to physically perform a surgery, they will typically be doing it.    Some patients find this alarming.   But they shouldn’t.

The problem is a misunderstanding about what doing surgery actually is.

Just like my high school mathematics misunderstanding, patients sometimes think that holding the knife is the top of surgery, the ultimate task.  The truth is that it is just the arithmetic.   When a resident operates, they are honing the physical skills they will need to one day operate without supervision, while the attending does the important work of deciding what needs to be done.  Attendings may not place every clamp and cut every pedicle, but they help the resident to do those things the right way, and when needed to redirect them away from the wrong things.  Sometimes that is just a gentle “why don’t you try doing it this way…” and sometimes its “lemme show you how to do that better.”  Sometimes its “you rock!” or “that’s great!  Now keep doing it that way the rest of your natural life.”

When senior residents struggle, it is rarely because they can’t physically do something, but rather that they do not know what should be done.  That’s when the attending steps in and redirects.  It is this intellectual work that is the core of surgery, what “doing surgery” actually is.  The physical task of cutting tissue, placing suture, and controlling bleeding is the arithmetic, not the calculus.   It is the building blocks that surgery is based on, not surgery itself.   Only once those buildling blocks have been mastered can the real learning of surgery begin.

I love teaching my junior residents the physical tasks of performing surgery, when I can wrest that work away from my senior residents.  It is great to see a third year resident that has taken those formative years and come out with great physical skills.  Still, it is even more satisfying to watch a senior resident who not only operates with good physical skills, but also makes good decisions in the operating room, and deals with an unexpected situation successfully.  But when they can’t, another attending or I will be there to help them make the right decision.   And because of that, when a patient asks me who will be operating, I can honestly say “Me”.

PS – To my residents and residents all over the world.   Learn the physical tasks of surgery outside of the operating room as much as you can.  Read one or more surgical textbooks cover to cover and know the material.  Understand suture materials.  Know the names of every instrument.  Tie knots at home five minutes every day until you can do it one and two handed, left or right dominant, in your sleep.  When an attending has to spend a case teaching you how to do these things, your chance of learning real surgery in that case goes way down.  But when you walk into the OR holding a knife right, understanding where sutures need to be placed in fascia, knowing where  figure of 8 should go to stop a bleeder, you can have the best cases ever.  If you work hard outside of the operating room, that will happen early in your residency.  If you don’t, it may not be until late in your third year or even fourth year, which hurts your ability to come out of residency as a solid surgeon.  If you are a medical student who wants to go into a surgical residency, its never too early to start.

Beyond use in the third world, this has potential application in developed nations as well, possibly replacing mosquito zappers forever!

See more video after the jump….

And of course, there’s already a parody in action.

Lots of people have been talking about Ulipristal acetate (Ellaone), a new emergency contraception option now available in the UK.  The buzz is that it is effective for 5 days instead of 3.

Currently in the US we have only one option for EC (Emergency Contraception): levonogestrel (Plan B), which is FDA labeled for use up to 72 hours after unprotected intercourse.  However, we now know that it is effective for up to 5 days after unprotected sex(1), though the efficacy seems to decrease the further out from the episode of intercourse you are.

It’s great to have a new EC option.  Having 2 options might help bring the price down (Plan B can range from $30 to $60 for one dose).  However, it may not be any better than what we already have.

A previous study published by Creinin et al demonstrated that Ulipristal was as effective as levonorgestrel (Plan B) at preventing pregnancy when used up to 72 hours after unprotected intercourse.  A subsequent study in the Green Journal suggested that Ulipristal had effectiveness up to 5 days, but no comparison to levonorgestrel was made(2).  This month, a study of Ulipristal was published in the Lancet  that compared Ulipristal to levonorgestrel in a randomized trial, showing and that it may be more effective than levonorgestrel in the 4-5 day time period(3).  However, the study design of this paper precludes us from making this conclusion definitively. And this is why you can’t just read the one-liner you see in the paper.

Statistics can be complicated, but basically this study was not designed to show that ulipristal was better than levonorgestrel, only to show that it was not worse.  In order to show conclusively that one drug is better than another, you need lots and lots of people to participate in the study.  This study had around 1900 women for the final analysis.  This seems like a lot, but only a small percentage of women in the study ended up being pregnant despite using either of the emergency contraceptive options.  In the group that took the new drug, ulipristal, there were a total of 15 pregnancies.  In the group that took levonorgestrel, there were a total of 25 pregnancies.  Those that took the newer drug were 40% less likely to become pregnant than those who took the older one.  It might seem that this shows that ulipristal is better.

Unfortunately, statistics is not that simple.  In life there are always random variations.  For instance, if you toss a coin 3 times, you might get 3 heads, 3 tails, or some other combination.  Whenever we do statistical calculations, we try to take into account that random variation by giving ourselves a range that we’re pretty sure the true answer lies within.  When the authors of this study did just that, they calculated that women who took ulipristal were anywhere from 70% less likely to get pregnant to 10% more likely to get pregnant.

The reason the researchers found themselves in this situation was that they never intended to prove the new drug was better, just that it wasn’t worse.  They would have had to recruit lots more women in order to prove that it was better (because the more people you have in your study, the less random variation there is).  But that costs time and money, and the pharmaceutical company didn’t want to spend extra money for this, especially if it turned out to be no better than the drug we already have.

Of note, they did perform a meta-analysis, which involves adding up the data from several different studies with the hopes of having more people to do the analysis on, therefore less random variation.  This method is fraught with difficulties, for reasons we won’t go into here.  They did find that it just barely was better than levonorgestrel at 72 hours and was significantly more effective at 120 hours.  However, as we said, this statistical method is very problematic.

Also problematic is that this research was paid for by the company that stands to profit from the results.  Such an arrangement can often lead to the company only allowing results that are favorable to be published and burying any results that are not favorable (we saw this with many anti-depressants in the ’90s).  Though we cannot avoid the need for industry funding at times, there are a number of mechanisms for limiting this type of bias.  This study was registered, as required, with ClinicalTrials.gov, a government trial tracking system that exists to limit non-publication of negative trials.  Lacking this registration requirement, it would be possible to bury a negative trial such that no one would ever knew it existed.  With this registration, it can be verified that a trial was performed but never published, disincentivizing non-publication of negative work.  Though this registration is important, also important is a study statement that says that the sponsoring entity (in this case HRA Pharma, the company that will market ulipristal) had no access to study data until the study was submitted to publication.  This precaution prevents any possibility of publication bias from the funding source.  This study unfortunately lacks this statement, and as such we do not know if this was the case.  As this study is authored by three physicians directly employed by HRA, it is fairly certain that the study data was known to HRA prior to publication.

The bottom line is that this is another option now available, it works at least as well as levonorgestrel, and might work better than levonorgestrel in the 3-5 day range, though that is unclear.  New contraceptive agents offer new choices to women for preventing unwanted pregnancy, and that’s a good thing all around.

The other bottom line is that the news media routinely misinterprets scientific studies and it’s important to have some knowledge of how statistics works in order to interpret such studies.

Sharon Phillips, MD

Nicholas Fogelson, MD

Dr Phillips is a Family Planning Fellow at Albert Einstein College of Medicine  / Montefiore Medical Center in Bronx, NY.

1.            von Hertzen H, Piaggio G, Ding J, Chen J, Song S, Bartfai G, et al. Low dose mifepristone and two regimens of levonorgestrel for emergency contraception: a WHO multicentre randomised trial. Lancet 2002 Dec 7;360(9348):1803-10.

2.            Creinin MD, Schlaff W, Archer DF, Wan L, Frezieres R, Thomas M, et al. Progesterone receptor modulator for emergency contraception: a randomized controlled trial. Obstet Gynecol 2006 Nov;108(5):1089-97.

3.            Glasier AF, Cameron ST, Fine PM, Logan SJ, Casale W, Van Horn J, et al. Ulipristal acetate versus levonorgestrel for emergency contraception: a randomised non-inferiority trial and meta-analysis. Lancet  Jan 28.

A patient was transferred to our service with a diagnosis of cervical ectopic pregnancy.  Her history was notable for two prior term vaginal deliveries without complications.  Ultrasound confirmed that she had a 6 week size pregnancy in the cervical canal with a fetal heart rate.  Consideration was given to several courses of action, including D and C versus treatment with methotrexate.   Due to concern for heavy bleeding with D and C, methotrexate was chosen.  Consideration was given to doing uterine artery embolization along with the D an C, based on a number of literature recommendations.

The patient was started on a multidose methotrexate regimen of 1 mg/kg every other day alternating with leukovorin rescue 0.1 mg/kg every other day.   Over the course of 4 treatments with MTX the Beta HCG rose from 8,000 to around 12,000 and then plateaued at that level.  The patient at that point was starting to have apthous ulcers from the MTX and preferred surgical management.

Due to the size and apparent accessibility of the pregnancy, a D and C was done without uterine artery embolization.   The cervix was injected with 10/40 vasopressin and a 7 mm suction was used to evacuate the cervix. After evacuation, a 30 cc foley was inflated with 10 cc of saline within the cervical canal.  The procedure was uncomplicated and there was very little bleeding.  The foley catheter was removed the next day and the patient was able to be discharged.   Beta HCGs would be followed to 0 in the outpatient setting.

Cervical ectopic pregnancy can be a very dangerous pregnancy, and if large enough can require greater intervention than was required in this case.  Large cervical ectopics can be difficult to separate from the underlying cervix.  Uterine artery embolization is recommended prior to attempted D and C of large cervical ectopics.  In some cases, hysterectomy can be required to control bleeding.  In this case, we felt that the chance for bleeding was very low due to the size of the pregnancy and the lack of cervical body dilatation.  The use of vasopressin is helpful in decreasing bleeding, and a tamponade balloon can also be helpful, though in this case it was probably redundant as there was little postoperative bleeding.

Academic OB/GYN Episode 15 – Green and Grey Journal January 2010

Recently there has been some discussion about the appropriateness of some of these images, particularly those that depict individual humans in despair or even in death.  Some have argued that such images should not be published without the express consent of the person depicted, or with the consent of the next-of-kin in cases of the dead.  Media, for the most part, has held that in cases of extreme human events the benefit of publicizing the truth outweighs whatever emotional harm might come to an individual through publication of their plight.  They argue that the many outweigh the few, in this case.

I have thought a great deal about this issue, both as it applies to the recent images in Haiti and to my own efforts at publication.  In this thinking I have formed the idea of unbalanced benefit in news reporting.  The point of news reporting is to explain to the world what is going on.  Ultimately this benefits the world, but may actually be of harm to the individual being reported on, though breach of confidentiality or publicizing of personal anguish.  Part of the issue is that sometimes a picture means something different to the person in the picture than it does to the stranger that views it.  If the world looks at a pile of dead bodies recovered from a collapsed building in Haiti, they see the situation that has occurred, and the overall effect it has had on the people and environment.   But if the mother of a dead woman in that pile of bodies sees the picture, its a whole different story.  That mother doesn’t see the overall situation, she sees her daughter, and knows that the world sees her too.   And so while the world may actually benefit from seeing that picture, and in turn Haiti may benefit from the attention it creates, the mother may suffer emotional distress because of it.   All without her consent.  Most media outlets feel that in situations like Haiti, consent is not required, if for any reason than it would be completely impractical.  To some this is hypocritical, as we certainly hold media to a higher standard when filming in the United States, hence the frequent blurred faces we see in some news broadcasts when consent for filming was denied or was not available.

So what about cases where an image is “nearly” anonymous?  The above example is one of these situations, where to nearly everyone in the world it is an image of random carnage, but to a select few it is an image of an individual person.   Is that image truly de-identified?  Does de-identified mean the same as unidentifiable?

I have been asking myself these questions a lot, as it relates to the publication of medical cases.  Recently I published several images from medical cases I was involved with, and all of these images have gotten significant traffic on the blog.  One in fact was immediately stolen and republished without consent or appropriate attribution on a Romanian OB/GYN blog, which I found concerning.

Before I published these images I thought a lot about whether or not it was a confidentiality issue.  Clearly none of them are identifiable to the world in general, but that doesn’t mean that they weren’t identifiable to the individual in the image.   That bothered me a bit, so I asked around to a lot of colleagues, who all seem to agree that de-identified images are kosher to publish.  After all,  pictures of interesting medical conditions are often taken in surgery, under the permission provided in most routine surgical consent forms.  Some of these pictures go on to be published in medical journals, all without any additional consent process taking place.  Furthermore, there are lots of websites that aggregate medical cases and publish de-identified pictures, and Google images is full of medical pictures.  Sermo is full of case reports with de-identified photos, which in some ways is different since everybody looking at the pictures is a physician.

It was always my intention that Academic OB/GYN would be a blog that would be trafficked mostly by OB/GYN physicians.  As the blog has developed, I have found that the traffic is far more mixed between physicians, other medical professionals, and laypeople.   So does this matter?   Is the implied de-identified publication right different when the audience that will look at the picture are not all doctors?   From a legal point of view, the answer is no.   In fact, HIPAA is pretty clear about what can be published and what cannot.

HIPAA specifies 18 elements that cannot be published without express patient consent:

1. Names;

2. All geographical subdivisions smaller than a State, including street address, city, county, precinct, zip code, and their equivalent geocodes, except for the initial three digits of a zip code, if according to the current publicly available data from the Bureau of the Census: (1) The geographic unit formed by combining all zip codes with the same three initial digits contains more than 20,000 people; and (2) The initial three digits of a zip code for all such geographic units containing 20,000 or fewer people is changed to 000.

3. All elements of dates (except year) for dates directly related to an individual, including birth date, admission date, discharge date, date of death; and all ages over 89 and all elements of dates (including year) indicative of such age, except that such ages and elements may be aggregated into a single category of age 90 or older;

4. Phone numbers;

5. Fax numbers;

6. Electronic mail addresses;

7. Social Security numbers;

8. Medical record numbers;

9. Health plan beneficiary numbers;

10. Account numbers;

11. Certificate/license numbers;

12. Vehicle identifiers and serial numbers, including license plate numbers;

13. Device identifiers and serial numbers;

14. Web Universal Resource Locators (URLs);

15. Internet Protocol (IP) address numbers;

16. Biometric identifiers, including finger and voice prints;

17. Full face photographic images and any comparable images; and

Any other unique identifying number, characteristic, or code (note this does not mean the unique code assigned by the investigator to code the data)

As such, the publication of a de-identified medical image along with general comments about the case, whether on the internet or in print, is a HIPAA compliant activity, and therefore should be kosher.  But still I am bothered by a few things.  HIPAA states that you can’t publish a patient’s zip code.  So does this also mean that there cannot be an implied zip code?  In my case, many people know who I am and where I work, so if I publish a case there is certainly an implied zip code, which may or may not be correct.  Certainly most cases I publish can be reasonably assumed to be my county or one of the adjacent counties. The same could be said for many case reports in journals, as they do list their city of origin.  Does this matter?   I’m not sure.

As I think about this, I realize that its not so different than the Haiti pictures.   To me and to my readers, a medical image is a picture of a condition, not of a specific person.  But in some cases, there is someone out there that might look at that picture and see a picture of themselves, and that bothers me.   It may not be illegal or HIPAA non-compliant, but it still seems wrong without explicit consent to publish a specific image.

It really comes down to this – if I were to ask a patient if they minded if I published a particular de-identified picture of them on a educational website and they said that they did mind, would I still want to have published it?  My answer is an emphatic NO.  If my patient saw a picture on the web that they realized was them, I would want them to feel happy that they are helping to educate someone, not upset that something was seen that they would have preferred be kept private, even if no one ever knew it was them.  I am not comfortable with the idea of unbalanced benefit when it comes to my blog.

As such, I’ve decided to change my photo policy.  As of now, I have taken down any picture that I believe an individual patient might be able to identify as a picture of themselves.  Furthermore, I will seek explicit written consent to republish these images, and will do the same prior to publishing any potentially self-identifiable case images in the future.  This will be a pain in the butt, but I think it is ultimately the right thing to do.  I challenge other medical bloggers to meet the same standards, which I think are ultimately just and reasonable for our patients.

DVTs are more common in pregnancy due to hypercoagulability of pregnancy, along with venous stasis from uterine compression.  In this patient we can see the classic mottling of the left leg along with generalized swelling. The black marks are the beginning and end of the thrombus found in the popliteal / femoral vein at doppler ultrasound.

After admission to the hospital, she felt something come out of her vagina and she started having heavy vaginal bleeding.  On exam she had a very large pedunculated fibroid.

Click the jump to see what we saw..

(***** This image has been temporarily removed but hopefully will be back soon ***** )

The patient reports that she had had some bleeding a year ago and had an exam which showed a mass in the vagina.   She was told she needed a hysterectomy but she never followed up.   Right after her heart attack, she felt a terrible pain like she was in labor, and passed this fibroid out the vagina.

As she had recently had an MI, we were hesitant to take this woman to the operating room, as general anesthesia in this situation carries significant risk.  However, over the next several days she bled enough to require 5 units of blood transfusion over 72 hours.   With that, coupled with the seeming ridiculousness of sending the woman home with the fibroid hanging out, we took her to the operating room and resected it.   We were able to do it was MAC anesthesia only, using a Harmonic Wave to resect the fibroid.  The uterus was partially inverted under the weight of this, so we used transabdominal ultrasound to locate the interface between the fibroid and the fundus, taking care not to perforate the fundus as the fibroid was resected.

After resection, the patient’s bleeding stopped and she felt better than she had in a long time, despite her heart attack.   Most likely she will have a hysterectomy in the future for fibroids that are residual in the uterus.

Pedunculated fibroids start as submucosal fibroids growing in the uterine cavity.   Typically they cause irregular and heavy bleeding, and lead to a woman presenting to a gynecologist for care.  If they are not taken care of, they can get quite large, as we see in this case.   Eventually, the weight of the fibroid will pull enough that a thin stalk is created.  As the uterus will try to “deliver” anything that is in it, these fibroids lead to heavy cramping as the uterus tries to push the thing out.  If the connection to the uterus is thin and stretchable enough, the uterus will eventually be successful, as we see in this case.  In many cases the uterus will partially invert as the fibroid delivers.  As such, the surgeon needs to take care not to perforate the uterus as the fibroid is resected.  If a vaginal hysterectomy is planned, the fibroid can be resected more distally and the stalk can be pushed up a bit prior to initiating the hysterectomy.  If not, the stalk should be transected as high as possible without entering the myometrium.  Hysteroscopy can be useful in some cases.

If you would like to use this prezi for your residents, let me know and I can send you the file.  All I ask is a mention of the blog in your presentation!

Enjoy!

Due to a death in the family I have not had much time recently to work on the blog and podcast.  I have not forgotten you all and all the support you have given, and am committed to making 2010 the biggest year yet for Academic OB/GYN!   But for the moment, it is on break.   I hope to get back to it in the next 3-4 weeks.

Be well,

Nicholas Fogelson, MD

Dr Onyeije

By Nicholas Fogelson, M.D. and Chukwuma Onyeije, M.D.

Early reports described the story of Tracy Hermanstorfer as a “Christmas Miracle”. It has also been described as  inspiring, heartwarming, and “wonderfully appropriate for the season.” Others have referred to her saga as a nightmare with a happy ending.

On Christmas Eve 2009, Ms. Hermanstorfer was admitted to Memorial Hospital in Colorado Spring, Colorado after her water broke.  Ms. Hermanstorfer suffered a cardiac arrest during labor with her child Colton.  After immediate resuscitative efforts failed, nearby Maternal Fetal Medicine physician (Dr Stephanie Martin) performed an emergency cesarean section.  In the minutes following the delivery, Ms Hermanstorfer regained circulation and breathing, and is now doing well. Her infant also went on to survive and is apparently well.

While it is clear that the heroic efforts from Dr. Martin and the team at Memorial Hospital were instrumental in saving two lives on the night before Christmas 2009, the story raises many questions. Some are satisfied to conclude that it was simply a miraculous event for which we should not expect an answer. Others are concerned about the chances that a perfectly healthy woman in childbirth could experience cardiac arrest. Finally, others will assume that there was some deviation from accepted practice at the hospital that lead to the events of that evening.

As expected, following this event, there has been a great deal of speculation what happened.   Many theories have been provided, but the underlying message in the mainstream media is that the reason for this event is, and will remain unknown.

The internet media has not been as humble.   There has been no shortage of conspiratorial theories and hypotheses in the blogosphere.  For the most part, such explorations into the cause of the Christmas Miracle are helpful as long as they are grounded in facts rather than opinion.  Many observers feel certain  that this event was due to a complication of an epidural, and used this reasoning to accuse the entire obstetrical model of malfeasance.  In comments on various sites, the authors of the current post entered the fray based initial accounts of the events, to state that we did not think this case was related to an epidural issue.  Our initial suspicions were  that Ms Hermanstorfer had a primary cardiac event of some kind.  Later accounts have provided a somewhat different story of the events, rekindling the possibility of an epidural issue.

As we have thought about this case in greater detail, we both recall one of the most important lessons in medicine:

When you are hearing about a medical case second hand, you never have the whole story.

Each of us can recall instances in which we heard about something that went amiss and felt that we had the answers that the people who were there were somehow lacking.  After giving these opinions in retrospect with some authority, we have both been humbled in finding that our initial impression was incorrect, when additional information became available.

These situations remind us that medical cases passed over voice communication are like a big game of telephone, and the details are always scrambled in the end.   The problem is magnified when information is carried by untrained people who often lack the medical knowledge to effectively communicate what happened in an unambiguous way.  Even medical charts can be ambiguous at times, particularly when they are constructed retrospectively after a critical event, when there is no time for contemporaneous documentation.

The truth is that what everybody has been talking about on the internet (present company included) is a theoretical case, based on information passed through multiple media sources about something that really happened.  Its like a movie based on a true story. They aren’t talking about the real Tracy and Colton Hermanstorfer.  The only people who can do that are the people who were there, and they have been the most humble of all, clearly admitting that despite a thorough workup they do not know what happened.

As outside observers, we do not have the answers to this case. However, as practicing OB/GYN physicians with experience in the field, we have the ability to use our familiarity with labor and delivery along with forensic research, review of the available information and some educated guesses to form hypotheses for what may have happened to Tracy.

All of the clinical information that we have at our disposal comes from the descriptions of the event in the media and online video interviews.  In order to provide our perspective to the current discussion, first let us go through what information we have about this theoretical case, and maybe create some educated theories on what might have occurred.

There have been a number of account of what happened, but mostly they come from an interview with Mr Hermanstorfer and ABC interviewer.

ABC – “You were holding her hand as Tracy got the epidural… when did you start to notice that there was a problem occurring.”

Mr Hermanstorfer – “Well we actually had her sitting up when she got the epidural and it wasn’t until afterwards that she laid down and said she was tired, and that’s when the nightmare started…. She started going numb and everything in her legs like you said and she laid down to close her eyes and take a nap…. We were in for a long day… and she wasn’t waking up.”

ABC – “When did you notice her breathing was getting shallow or her fingers were getting blue?”

Mr Hermanstorfer – “When I felt her hand it started getting cold, and one of the nurses noticed that the color in her face was completely gone, she was gray as a ghost.”

Following these events, resuscitative efforts started.  30-45 seconds after nearby Dr Martin arrived Tracy’s heart stopped.  A cesarean was performed a few minutes later, and at some point after delivery Tracy recovered a heartbeat.

A number of physicians have been called upon to speculate on what occurred, but no physician has yet claimed to know exactly what happened, outside of saying that she experienced a cardiac arrest.  Childbirth Educator Henci Goer, on the other hand, has decided that this was certainly the result of a high spinal anesthetic that lead to respiratory collapse and cardiac arrest.

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So let’s go through a few possibilities, how they happen, and why or why not they might have occurred here.

HIGH SPINAL ANESTHESIA

A high spinal anesthetic occurs when anesthetic drugs intended to remain in the lower part of the spinal cord travel up to the top of the cord, creating greater anesthesia and paralysis than is intended.  This can occur either in the epidural space, above the duramater, where an epidural catheter is supposed to be, or in the subarachnoid space, beneath the durameter, where the catheter can (rarely) be inadvertently placed.

A high spinal has a characteristic presentation.   With a high spinal, after  dosage of the spinal or epidural anesthetic the patient’s level of numbness and weakness progressively rises.  Once it reaches the level of the chest, some of the breathing muscles become paralyzed, giving the patient the sensation of not being able to breathe, despite continued motion of the diaphragm.  If the level reaches C3, the diaphragm will become paralyzed, rendering the patient unable to breathe.  A high enough spinal also blocks the sympathetic nervous system, which speeds up the heart and is part of how we maintain blood pressure.  This can lead to lower blood pressure and pulse rate.  All of these things together, if untreated, could eventually lead to a cardiac arrest.  The medical literature does describe cases of cardiac arrest following high spinals.

After reviewing what information we have, we feel it is possible that this is what happened in this case.  However, there are some problems with this theory.   First of all, if this had occurred, Ms Hermanstorfer would have had progressive shortness of breath and eventual respiratory collapse.  Nothing in the transcripts indicates that this happened.  The only mention of “shallow breathing” is by the interviewer, and was not corroborated by any source that was actually there.  In fact, no-one but the interviewer ever mentioned shortness of breath at all.  Her husband mentioned that she felt tired and wanted to go to sleep, which is not what someone short of breath would do.  In fact, shortness of breath is a very strong stimulator of the central nervous system, and nobody would want to sleep in that state.

And most telling, there is not one mention of a high spinal anywhere in any story, nor by the physicians treating the patient, or by physician commenters.   A high spinal is something that is not hard to recognize.  If it had happened, we wouldn’t be talking about a mystery at all – and if it had made the news at all it would have been reported as such.

LIDOCAINE TOXICITY FROM EPIDURAL ANESTHESIA

A rare complication of epidural placement is placement of the epidural catheter into a small vessel in the epidural space.  If this is done, the local anesthetic lidcoaine can be infused directly into the venous system and thus into the heart.  In adequate quantities, this can cause cardiac arrest.

Some have speculated that this might have occurred, and it is worth considering.   But there are two big problems with this theory.  First, it is standard procedure when placing an epidural to use a test dose of anesthetic mixed with some epinephrine.  If the catheter is intravascular, that small amount of epinephrine will quickly cause tachycardia, alerting the anesthesiologist of the issue.  We don’t know if that was done in this case, but most likely it was.   The other issue is that like the high spinal issue, this case doesn’t really fit a lidocaine poisoning profile.   Lidocaine toxicity can cause cardiac arrest, but first it causes seizures.  Ms Hermanstorfer did not have seizures.

PRIMARY ARRYTHMIA

It is possible that Ms Hermanstorfer had a primary cardiac arrythmia, possibly due to a congenital heart defect or conduction pathway aberration.  I imagine that this has since been investigated with tests to evaluate the structure and function of her heart such as an EKG and an echocardiogram.

AORTOCAVAL COMPRESSION

Aortocaval compression syndrome, is a condition caused by the compression of the two major blood vessels in the back of the mothers abdomen (the abdominal aorta and inferior vena cava) by the pregnant uterus when a woman lies on her back.  Aortocaval compression is a frequent cause of low maternal blood pressure, which can in result in loss of consciousness.  In extreme circumstances it can also lead to a significant decrease in blood flow from the mother’s heart which can result in cardiac arrest and fetal demise.

Symptoms that precede loss of consciousness from aortocaval compression include  a rapid heart beat, sweating, nausea, low blood pressure and dizziness.  Aortocaval compression is very common in pregnant patients and would not be related to anesthesia.  However, it would be extremely rare for aortocaval compression to result in cardiac arrest as seen in this case.

AMNIOTIC FLUID EMBOLISM

An amniotic fluid embolism occurs when amniotic fluid enters the maternal vascular system.  This can cause massive cardiovascular problems, including sudden cardiac death, even in very small amounts.  This is certainly high on the list of what could have occurred in this case.  Some have claimed that her lack of bleeding and clotting abnormalities rule out this possibility, but we would point out that we actually don’t have this information.  She very well may have had some of those signs later.  Though a large embolism does reliably cause more long term illness, a very small one could present this way.    AFE is a very difficult thing to study, as large ones are frequently fatal, and non-fatal ones are hard to confirm, as the only real confirmation is through autopsy.  Thankfully we are spared that confirmation in that case, and so this possibility remains.

PULMONARY EMBOLISM

This is when a clot breaks off inside a vein, usually a leg vein, and ends up in the lungs.  A large enough clot can block all blood flow out of the heart in the lungs (called a Saddle Embolus), causing cardiac arrest and sudden death.  Though this was mentioned by a few newscasts, the fact that she did not have persistent shortness of breath and hypoxia after the recovery pretty much rules this out.  A small embolus wouldn’t have stopped her heart, and she would not have recovered quickly from a long one.

AIR EMBOLISM

This is when a large amount of air gets into the venous system.  This can act very much like a  pulmonary embolism, as it can block blood flow through the heart.  However, as the major components of air are blood soluble, this typically will be absorbed and the patient will recover.  The question in this case would be how the air got into the system, if that were what occurred.  Epidurals and IVs can’t deliver enough air to cause this issue.  If her membranes had been ruptured, this could have happened through the uterus, but that would be a very strange occurrence.   But this case is strange, so who knows.

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Finally, we think it is prudent to clear up some misconceptions which have been propagated in the media reports of this case.  The first issue concerns the status of the child at birth.  Some reports have indicated that the child was born lifeless and that the resuscitation of the infant was part of the miracle of the birth.  While we cannot deny the fact that it is a beautiful thing that Colton survived this harrowing birth, we do feel that it is not fair to the pediatric staff who performed the resuscitation to simply dismiss their actions as a byproduct of some larger miracle.  Indeed, when a fetus has an abnormal heart rate or a delivery is done as an emergency, it is not uncommon for the child to appear “lifeless” at birth.  It is a testament to the diligence and professionalism of pediatric care specialists that such infants are routinely resuscitated successfully at the time of delivery.

Secondly, many reports which have indicated that Ms. Hermanstorfer “died” and then came back to life miraculously.  While this certainly makes for sensational headlines, physicians are reluctant to make such claims.  Certainly when a persons heart stops beating, there is a presumption of cessation of life, but it is important to distinguish clinical death/cardiac arrest (which is reversible via CPR and other medical procedures) from biological death (which has no cure from a medical standpoint).  Tracy was clinically dead but not biologically dead.

It is possible (as Dr. Martin has indicated) that the act of delivering the fetus relieved pressure on the aorta and vena cava and provided the impetus for Ms Hermanstorfer’s heart to resume beating.  There is also a condition known as electromechanical dissociation in which the electrical activity of the heart continues but cannot be detected in the patient’s heart beat or pulse.

Another important issue concerns the time that Ms Hermanstorfer was in cardiac arrest.  Initial reports indicated a period of 15 minutes; however, subsequent interviews with Dr. Martin suggested 4 to 5 minutes.  This 10 minute difference is huge from a medical perspective because the likelihood of reversing cardiac arrest drops significantly the longer a person is in arrest.

In the end, we have an insufficient amount of information to determine why the “Christmas Miracle” occurred.  Based on what we know, the  most likely cause is either is an unusual form of aortocaval compression or a  primary cardiac arrythmia leading to cardiac arrest.  These conditions are highest on the list of medical problems that would lead to such rapid decline, and potentially recover as was seen in  this case.

Although we cannot say whether this case could have or should have been handled differently, we join with others in congratulating the medical staff at Memorial Hospital in Colorado Spring, for their rapid, life-saving action and wish all of the best to Tracy, Colton and their family.

Nicholas Fogelson, MD

Chukwuma Onyeije, MD

As the transdermal patch was a new delivery method for birth control, several new pharmacokinetic studies were done postmarketing, in addition to those done prior to FDA approval.  One of these studies demonstrated that patients using Ortho Evra had on average 60% higher estrogen blood levels than patients on oral contraceptives, despite lower peak levels (1).  Given that estrogen somewhat increases the risk of venous thromboembolism(VTE), this data raised the concern that Ortho Evra might confer a greater attributable risk than traditional oral contraceptives.

Due to this concern, several studies were performed and published with mixed results.   In 2006, a case control study was done that demonstrated no additional risk for VTE with Ortho Evra as compared to oral contraceptives (2).  In 2007, a retrospective cohort study showed that the risk of VTE with Ortho Evra was double what it was with oral contraceptives (3).   And this month in Contraception Jick et al reported an updated case control study that demonstrated that Ortho Evra was not associated with an increased risk of venous thromboembolism when compared to oral contraceptives (4).

After reading this new paper, I was intrigued and wanted to review all the data.  And per usual, when I do this I like to get a blog post out of it.  So lets look at the data!

2006 – Jick et al reported case-control data based on data collected by PharMetrics, a company that reports data based on clinical service and pharmaceutical insurance claims.  This study compared 68 new cases of VTE (cases) with 266 women (controls) who did not experience VTE, from a pool of women who had recently started either Ortho Evra or a norgestimate containing oral contraceptive (Ortho Tri Cyclen, Trinessa, Sprintec, and a few others.)  All cases and controls were new starts of their contraceptives during the study period.  Cases were identified based on diagnosis codes indicating that venous thromboembolism had occurred (DVT, Pulmonary Embolism) and were confirmed with evidence of subsequent long term anticoagulation.  Chart abstraction was not performed.   Medication exposure was identified based on prescription histories.

In this case control analysis, Ortho Evra was found not to be associated with an increased risk of VTE in comparison to OCPs, with an odds ratio of 0.9 (95% CI 0.5 – 1.6.)

2007 – Cole et al reported a different study, with a different data set and methodology.  This study was also based on insurance records, but instead of a case-control analysis a retrospective cohort study was done (Cohort: Exposure -> outcome vs Case-Control: Outcome -> Exposure).   49,048 woman-years of Ortho Evra exposure were compared to 02,344 woman-years of norgestimate OCPs were compared in their frequency of VTE, myocardial infarction, and stroke. Events were identified via diagnosis code search, but all positive outcomes were confirmed by chart abstraction and verification.  A nested case-control design was used to confirm similarity of the two groups to investigate demographic difference between affected and unaffected women.

This study found a different result than the 2006 data from Jick.  It demonstrated a more than two-fold increase in the rate of VTE in Ortho Evra users in comparison to OCP users (Relative Risk 2.2 95% CI 1.3-3.8).

2010 – Jick et al, reporting an expanded dataset of the 2006 study, and an additional analysis based on a new insurance dataset.   Study design was quite similar to the 2006 study.  Again, no increased rate of VTE was found with Ortho Evra users in comparison to OCP users, with an odds ratio of 2.0 (95% CI 0.9 – 4.1) for one dataset and 1.3 (0.8 – 2.1) for the other dataset.

So what the hell?   We have three different studies and no clear answer.   And this brings me to my first major point.

There is a correct answer. Ortho Evra is either associated with a greater risk of VTE than oral contraceptives or it isn’t.  They can’t both be true.  Therefore, one or more of the studies has an incorrect answer.

So there are two ways a study can be incorrect: 1) statistical error and 2) bias.

Statistical error would be based on pure mathematics.  Most studies are powered to have a 80% beta, or 80% chance of finding and difference between groups if there is one, and a 95% alpha, or a 95% chance that if there is no difference between groups none will be found.  If this sounds a bit like my descriptions of sensitivity and specificity in the last post, that is because alpha and beta are just different ways of referring to those concepts.

So a study can be wrong just because the numbers don’t work out.  Sometimes, based on statistical power, it gets the wrong answer.  Typically those studies will get the correct answer if they are repeated, as the chance of hitting the wrong one is low.  This is why any study worth doing is worth doing many times, which is what we generally do.

But bias is different.  Bias is not about mathematics.  It’s about a study design that systematically favors one outcome over another.   Sometimes a study is done twenty times and gets the same result, but because of bias and similar study design, all twenty results are wrong.   Bias, unlike stastistical error, cannot be overcome with increased study power or study repetition.

So we have three different studies that have two different answers.   At least one is wrong, and it is wrong either because of bias or statistics.

In this case, its bias.

Both studies by Jick have a fundamental study design error that biases the result.  Jick and the other authors noted that the use of Ortho Evra increased dramatically over the study period, and the use of OCPs decreased.  They felt that this might create bias in their outcome due to differing availability of the two drugs over the study period, so they decided to control this by making sure that every case and control was a new start on their method of choice.   I believe this badly biased their results.

If a patient was exposed to oral contraceptives as a new start, they were likely on nothing before, as there weren’t a lot of options before.   But if patient was exposed to Ortho Evra, they could have been on oral contraceptives before.  This created a bias.  Patients exposed to OCPs were way more likely to never have been exposed to a contraceptive, and therefore never have had the opportunity to have a estrogen related VTE.  Women on Ortho Evra, on the other hand, likely had been on OCPs before, and therefore did have an opportunity to have a prior OCP related VTE.  And if they had had that, they never would have used the Ortho Evra.  As such, the Ortho Evra exposed women in the study were actually a subset of all women that might have used Ortho Evra – they are women who used Ortho Evra who had already demonstrated the ability to not have a DVT on oral pills.  As DVT risk certainly has a large genetic component, this really skews this group, and systematically decreases the likelihood that VTE cases would have been exposed to Ortho Evra.  Ultimately, I think this is why Jick did not find a difference in VTE for Ortho Evra users, and lacking this bias, why Cole did.   Jick was concerned about the differing availability of the two drugs over the study period, but I believe this should have been controlled for in another way that would not have introduced a bias in favor of Ortho Evra.

So of these three studies, I believe the Cole data, and doubt the Jick data.  So I think that Ortho Evra does indeed increase VTE risk relative to OCPs, which makes the most sense, as it does have a higher level of estrogen exposure than OCPs.

So now for the second point –

You can’t trust abstracts alone. All three of these studies, if you just read the abstracts, appear to be properly done.   That’s because the abstract is just a tiny little summary of the entire manuscript, and says very little about study design  The abstract is paragraphs and the manuscript is six to ten single spaced pages.

In order to really understand a study, you have to read the whole thing.   And importantly, the first thing you have to look at is the Materials and Methods – how they did the study.  Only if the study is properly powered and does not have systematic bias should you really trust the conclusion.

I bring this up because of something I have noticed – the lay public is starting to read our papers, and often misunderstanding them.  I think that’s great (I really do), but I have to make this warning.   If you have not really trained in study design and analysis, its really hard to really know what medical papers say and which ones you can trust.   If you are one of my layperson audience and want to read medical papers, I implore you to spend some time learning how to read papers.  There are many references on this, but the single best volume I can recommend is a small book by David Grimes and Ken Shulz entitled “Handbook of Essential Concepts in Clinical Research” It is a fantastic book that is easy to read and will teach one all one needs to know to appropriately assess the quality and results of a paper.  I’m going to try to cover some points in future blog posts as well.

The other problem is that it can be hard to get the full manuscripts.  This is because medical journals have a completely different business model than regular magazines.   Unlike lay press that is supported by advertising, journals are supported by subscription fees.  A subscription to a journal is often several hundred dollars a year.  Medical libraries spend hundreds of thousands and sometimes millions of dollars a year maintaining an appropriately broad collection.  It would be great if journals made their content free to all, but as they have little advertising dollars, they would not make any money and could not exist. As a physician, I have access to a medical library and can get whatever I want online.  But laypeople lack this access.

So what should you do if you are not one of my physician or scientist readers?   Go read journals at your local hospital or library.  Every hospital has a library, and large hospitals have really big libraries.  Teaching hospitals may even have a university library that is just huge.  Usually you can get access to these libraries for free, and read all the journals you like.

It’s a bit of an effort, but if you want to read medical literature, you have to read the whole thing, and learn how to read it.   Abstracts aren’t enough.

1. van den Heuvel MW, van Bragt AJ, Alnabawy AK, Kaptein MC. Comparison of ethinylestradiol pharmacokinetics in three hormonal contraceptive formulations: the vaginal ring, the transdermal patch and an oral contraceptive. Contraception 2005 Sep;72(3):168-74.

2. Jick SS, Kaye JA, Russmann S, Jick H. Risk of nonfatal venous thromboembolism in women using a contraceptive transdermal patch and oral contraceptives containing norgestimate and 35 microg of ethinyl estradiol. Contraception 2006 Mar;73(3):223-8.

3. Cole JA, Norman H, Doherty M, Walker AM. Venous thromboembolism, myocardial infarction, and stroke among transdermal contraceptive system users. Obstet Gynecol 2007 Feb;109(2 Pt 1):339-46.

4. Jick SS, Hagberg KW, Hernandez RK, Kaye JA. Postmarketing study of ORTHO EVRA and levonorgestrel oral contraceptives containing hormonal contraceptives with 30 mcg of ethinyl estradiol in relation to nonfatal venous thromboembolism. Contraception  Jan;81(1):16-21.

PS Ortho Evra is still a great birth control method for many women.  Any estrogen birth control method increases VTE risk, but the effect is small.  Pregnancy also increases VTE risk.

Let’s take the example we have been working with about cesareans for protracted labor, and see if we can think about an ROC for the decision on whether or not to do a cesarean.   Consider two populations of women: 1) women who given enough time, will deliver a healthy baby and 2) women who bear a baby who will given enough time, will be injured in utero or will deliver vaginally but injured or dead.  Now, consider the decision of whether or not to do a cesarean delivery.  If this decision (the test) is to do a cesarean, we would say that the test was positive, and if the decision were to await a vaginal delivery, we would say that test is negative.   A cesarean delivery for dystocia done in group 2 would be a correct decision (a true positive).  A cesarean delivery done in group 1 would be an incorrect decision (a false positive).  Waiting for vaginal delivery in group 1 would be the correct move (a true negative), and waiting for vaginal delivery in group 2 would be the wrong move (a false negative).

So what about ROC.   ROC is a graph of the sensitivity of a test versus the inverse of its specificity.  OK its getting confusing already, and that’s why ROC is a little hard to understand.

Sensitivity is the likelihood that the test will correctly identify those with a condition (likelihood that babies that need to be delivered by cesarean to be uninjured will get a cesarean), and specificity is the likelihood that the test will correctly identify those without the condition (likelihood that those who will eventually deliver vaginally uninjured will not get a cesarean).

Sensitivity and specificity of a test depend on the cutoff value that one chooses to put on the test – that is where the line is that defines positive versus negative.  In a case like iron deficiency which can be defined objectively, we could have a objective cutoff like a ferritin of 100, and decide that those under 100 test positive and those over 100 test negative.  Then we could compare those results to some gold standard, like bone marrow iron stores, and decide what the sensitivity and specificity were.  We could then look at what they would have been if the cutoff had been 50.   And again at 150.  And again at 10, and then 20, and then 30, and so on.   And when we graphed all those points, what would we have?   A ROC!

In the cesarean example, it is a little more obscure, but in some ways more apropos to real medical decision making.  In this case, the cutoff is not a objective value, but an internal thought process of how convinced we are going to need to be before we will take action.   Are we going to do a cesarean at the first sign of trouble (way out towards sensitivity) or are we going to wait for a really terrible strip, or a woman arrested for 12 hours, before we go to the operating room (way out towards specificity.)

Ulimately the ROC describes just how good a test is.   It describes the interplay between sensitivity and specificity, how much of one we have to give up to get some of the other.   If a test is great, we may be able to get very high specificity and sensitivity at the same time.  If a test is not as great, we may only be able to have one at a time, depending on what cutoff value we choose to use.

Here is an example of a ROC for a typical medical test, where sensitivity and specificity are traded for one another at different thresholds.

At point 6, we have nearly 100% specificity, but only 50% sensitivity.  At point 3 we have 70% specificity, but 90% sensitivity.

One can see that the closer that line hugs the left and top parts of the graph, the better the test will be; the more sensitivity and specificity one can simulataneously have.

So why does this all matter in the cesarean section case?   Because it demonstrates that there is no absolute to these decisions.   Some commenters have tried to make the case that many cesareans are unecessary, and they are of course correct.  Some commenters have made the case that most cesareans are necessary, and they are correct as well.   It all depends on where you put your cutpoint, and what the ROC for the decision looks like.

If our #1 outcome is to prevent any neonatal injury from intrapartum asphyxia and infection, we could do cesareans for everybody, at the expense of doing many cesareans that were not necessary.  That would be running our setpoint all the way on the right side of the ROC.   If our goal was to prevent every cesarean but the ones that were obviously necessary, we could run all the way on the left, doing the minimum number, but also failing to do cesareans for babies that might have ultimately needed them.

For this particular problem, we don’t know exactly what the ROC looks like, because we don’t have a gold standard test that can tell us what will happen to a baby if it is or is not delivered by cesarean.   But this idea illustrates some of the difference between me and the OB/GYN commenters and some of the midwifery and doula commenters.   OB/GYNs tend to run their setpoint further to the right on the ROC, and midwives and doulas prefer to run further on the left.   OB/GYNs go for sensitivity, while the midwives and doulas go for specificity.

In complex decision making, this idea is crucial.  Any time you change your decision threshold, you will trade sensitivity for specificity.  To make a good decision, one has to be honest about what one fears most: a false positive or a false negative.   In OB/GYN, we fear the false negative of the baby that needed a cesarean, that we failed to perform.   And that’s why we tend to run to the right.  Perhaps a little too far, as I have suggested before.

Academic OB/GYN Episode 14 – Cardiovascular Disease Markers in Women

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Academic OB/GYN Episode 13 – Green Journal November-December 2009

The underlying fetal concern is that in very rare cases, the previous uterine scar can rupture in labor, which can result in fetal injury or death.  Most large series demonstrate a risk if about 0.5% in natural labor, and about 1% in pitocin augmented labor, assuming that the woman has had a single low transverse hysterotomy (cesarean scar.)  These risks increase for low vertical hysterotomies (1-3%) and even further for high vertical (classical) scars.  Some large series have shown slightly lower or higher rupture rates. In cases of uterine rupture that happen in hospital, most patients can successfully have a emergent cesarean delivery and deliver an uninjured baby, but in some cases (10-20%) there will be fetal injury or death.  This risk can be eliminated by choosing to do repeat cesarean deliveries prior to labor.

But there is another side to this coin.   Choosing repeat cesarean is less risky for the infant, but now exposes the mother to surgical risk and recovery issues that would be avoided with a successful VBAC.  While generally safe in any one case, in aggregate cesarean delivery exposes the mother to small but real risks of significant complications.  Minor risks include wound infection or separation, while more major risks include severe bleeding requiring transfusion, hysterectomy, or even death.  These major risks are very rare, but when looking at thousands of cases we will see them.  Furthermore, any woman who has a repeat cesarean delivery has a longer recovery course and more pain than a woman who is able to successfully have a VBAC, and may have other problems such as breastfeeding difficulty.

So here are a few of my thoughts on this issue:

1) VBACs are unquestionably higher risk than routine vaginal deliveries.  Though the risk of uterine rupture is small, it is real, and should not be ignored.  ACOG recommends that VBACs occur in hospital where there is in house anesthesia and obstetrics and the ability to emergently perform a cesarean delivery.  This is a wise recommendation, and should be followed.   Uterine rupture can be managed by an efficient and skilled team, but if things are not handled quickly and correctly it can result in severe fetal injury or death.  We should not forget that.

2) VBAC should not happen at home.   I have recently referred to that as a game of Russian Roulette, and defend that view here.   In this case the gun has 100 barrels, but the bullet will kill the baby just the same.  If a woman can honestly say they are willing to take a 0.5% to 1% risk of disaster, then fine, but to me that risk is way too high.  I think home birth is an acceptable option in many cases, but VBAC is not one of them.

3) VBAC should be encouraged when the facilities are available.  It is a  shame when doctors who work in facilities that have the ability to provide VBAC services aren’t willing to do this.  It is also a shame if doctors overemphasize the fetal risks of VBAC, which are minimal if properly managed.

4) Those that fight for VBAC rights need to understand that physicians are under great pressure from malpractice carriers, and in some cases hospitals, to not provide VBAC.   Malpractice carriers in some cases will not allow their covered physicians to VBAC, as uterine ruptures are unpredictable and carry a high risk of litigation if they occur, despite thorough informed consent prior to the VBAC attempt.  Hospitals also accept liability by providing VBAC services, which amounts to financial payout, without getting much in return.  When they provide VBAC services they do so in order to provide more comprehensive care, but do so at some liability risk.  It is important to understand that given legal liability, doctors and hospitals are encouraged to take predictable risks (cesarean complications) over unpredictable risks (uterine ruptures.)  Legal protection for physicians and hospitals who have predictable VBAC complications would go a long way to increasing VBAC availability.

5) Physicians also must stay in or near the hospital when a VBAC attempt is going on, which can be logistically difficult.  Obviously midwives don’t have this problem, but midwives also can’t do the emergent cesarean delivery if it were needed.  The reality is that for a small private practice physician to stay in house for an entire VBAC labor likely costs that physician several thousand dollars in income, and all the while his or her office overhead continues to accrue.  This is avoided in large groups that have a permanent in house covering physician or academic practices, but in small practices this can make VBAC very difficult to work into a practice.

6) The choice whether or not to VBAC has a lot of things that goes into it.  The number of children a woman wants to have is a big issue.  If a woman plans only 1 more child after her first cesarean, the absolute risk to that woman is very low with her first repeat.  Risks start to rise substantially as she has more repeat cesareans, so a woman who plans 5-6 children gets a relatively greater benefit from the first successful VBACs (and presumably subsequent VBACs) than the woman who has only 1 VBAC.  A woman who wants to be sterilized is sometimes encouraged to have a repeat cesarean and sterilization at one time, but I would not recommend this.   Hysteroscopic sterilization can be done after a successful VBAC at 10x less risk than an open procedure (though risks for either are very low.).

7) VBAC success rates are difficult to predict, and vary greatly on the provider who is deciding when to quit and do a cesarean.  There are many models for calculating success rates out there, but are difficult to extrapolate to different providers.  Women who had a cesarean for breech tend to have the highest VBAC rates, then women with cesarean for fetal distress, then women for cesarean for arrested labor.  Importantly, even the lowest success rate groups have a 60-65% or greater chance of successful VBAC in most series, which is not substantially higher than underlying cesarean rates.   There is very little evidence that we can predict VBAC failure reliably in any woman, and substantial evidence that the majority of women can successfully VBAC.

8 ) It is unlikely that rural (and some semi-rural) areas will have VBAC access, due to the infrastructure that is required to provide it.   We can lament this all we want, but this is a reality that is unlikely to change.

9) Given the current medicolegal climate, some women may need to travel some to do a VBAC in a hospital that has the infrastructure to provide it.  Having a VBAC in a hospital not equipped to handle a uterine rupture quickly and efficiently is a bad idea.

10) The single most important thing we can do to deal with VBAC issues is to not have them at all, by avoiding the first cesarean section.  Many cesareans are absolutely necessary, but when possible we should achieve vaginal deliveries.  I’m willing to push some grey cases that others might deliver by cesarean.  Sometimes that means being more patient with a slow labor.  Sometimes that means operative vaginal delivery.  Because of that, more of my patients will have easy multiparous second labors rather than having to worry about VBAC issues.  There is a receiver operator curve for cesarean necessity.  Most OBs should push their needle a little towards “specificity”.

Bottom line – using a paracervical block during second trimester abortion done under general anesthesia does not affect postoperative pain scores.

Impact of paracervical block on postabortion pain in patients undergoing abortion under general anesthesia.  Lazenby GB, Fogelson NS, Aeby T.  Contraception. 2009 Dec; 80(6):578.82.  Epub 2009 Jul 10.

Episiotomy was supported in Medline indexed publications as early as the 1920s(1), and many publications followed in support of this procedure.  But by as early as the 1940s, publications began to appear that argued that episiotomy was not such a good thing(2).  Over the years the mix of publications changed, now the vast majority of recent publications on episiotomy focus on the problems with the procedure, and lament why older physicians are still doing them (3) (4).  And over all this time, practice began to change.

It took a long time for this change to occur, and a lot of data had to accumulate and be absorbed by young inquisitive minds before we got to where we are today, with the majority of recently trained OBs and midwives now reserving episiotomy only for rare indicated situations.

Though this change in episiotomy seems behind us, there are many changes that are ahead of us.   One of these changes, I believe, is in the way obstetricians handle the timing of cord clamping.

For the majority of my career, I routinely clamped and cut the umbilical cord as soon as it was reasonable.   Occasionally a patient would want me to wait to clamp and cut for some arbitrary amount of time, and I would wait, but in my mind this was just humoring the patient and keeping good relations.  After all, I had seen all my attendings and upper level residents clamp and cut right away, so it must be the right thing, right?

Later in my career I was exposed to enough other-thinking minds to consider that maybe this practice was not right.   And after some research I found that there was some pretty compelling evidence that indeed, early clamping is harmful for the baby.  So much evidence in fact, that I am a bit surprised that as a community, OBs in the US have not developed a culture of delayed routine cord clamping for neonatal benefit.

I think that this is a part of our culture that should change.  This evidence is compelling enough that I feel like a real effort should be made in this regard.   So to do my part in this, I am blogging about it.

As this is Academic OB/GYN, of course I am going to lay out this evidence I speak of.  But before I do that, I want to present some logical ideas under which this evidence ought to be considered.

Prior to the advent of medical delivery, and for all time in animals, it has been the natural way of things for a baby to stay on the umbilical cord for a significant period of time after delivery.  Depending on culture and situation, the delay in cord separation could be a few minutes or even a few hours.  In some cultures the placenta is left on for days, which of course I find excessive and gross (5).  But whatever the culture and time on cord, the absence of immediate cord clamping allows fetal blood that was previously in the placenta to transfuse back into the baby.  Studies have demonstrated that a delay of as little as thirty seconds between delivery and cord clamping can result in 20-40 ml*kg-1 of blood entering the fetus from the placenta (6).

Considering this data, I have to think about evolution and function.  I am a strong believer in evolution, but even under creationist thinking I have to believe that if the system meant for babies to have been phlebotomized of 50-100 cc of blood at birth, we would have been born with higher hemoglobins.  Clearly the natural way of things is for this not to happen.

So does this mean that early cord clamping is necessarily harmful?  Absolutely not.   But what it means is that the burden of proof is on us to prove that early cord clamping, which amounts to planned fetal phlebotomy, is a beneficial thing.  Otherwise, all things being equal we ought to give the tykes a few minutes to soak up what blood they can from the placenta before we cut’em off.

So the question is whether or not there is strong data either way.

It is easy to imagine a randomized study of immediate vs. delayed cord clamping, with quantitative analysis of fetal lab values and clinical outcomes.  So easy in fact, that it has been done many times – and in just about every study, there is a clear benefit to delaying cord clamping, even if it is just for 30 seconds after delivery.  These benefits include important outcomes such as decreased rates of intraventricular hemorrhage and necrotizing enterocolitis in preterm neonates.  Furthermore, aside from some intermittent reports of clinically insignificant polycythemia and hyperbilirubinemia in term infants, there appears to be no harm that can be linked to delayed cord clamping. It feels like being a doctor 10-15 years ago looking to see if there is any data about episiotomy, and finding that there’s a lot, and it says we’ve been doing it wrong for awhile now.

So here’s the data:

Delayed cord clamping in very preterm infants reduces the incidence of intraventricular hemorrhage and late-onset sepsis: a randomized, controlled trial(7)

Randomized 72 VLBW infants (< 1500 grams) to immediate or delayed cord clamping (5-10 vs. 30-45 seconds).  Delayed cord clamp infants had significantly less IVH (5/36 in delayed group vs. 13/36 in immediate group, p = 0.03) and less late onset sepsis (1/36 vs. 8/36, p = 0.03).

The Influence of the Timing of Cord Clamping on Postnatal Cerebral Oxygenation in Preterm Neonates: A Randomized, Controlled Trial (8)

Randomized 39 preterm infants to immediate clamping vs. 60-90 second delay, and examined fetal brain blood flow and tissue oxygenation.  Results showed similar blood flow between groups, but increased tissue oxygenation in the delayed group and 4 and 24 hours after birth.

Effect of timing of umbilical cord clamping on iron status in Mexican infants: a randomized controlled trial(9)

Randomized 476 infants to immediate or 2 minute delayed clamping and followed them for 6 months.  Delayed clamped babies had higher MCVs (81 vs. 79.5), higher ferritins (50.7 vs. 34.4), and higher total body iron.  Effects were greater in infants born to iron deficient mothers.  Delayed clamping increased total iron stores by 27-47mg.  A follow up study showed that lead exposed infants with delayed clamping also had lower serum lead levels than immediate clamped infants, likely due to iron mediates changes in lead absorption.

A randomized clinical trial comparing immediate versus delayed clamping of the umbilical cord in preterm infants: short-term clinical and laboratory endpoints(10)

Infants delivering at 30 to 36 weeks gestation randomized to immediate vs. 1 minute delay.  Delayed group had higher RBC volumes (p = 0.04) and hematocrits (p < 0.005), though there was no difference in RBC transfusions.  There was a small increase in babies requiring phototherapy in the delayed group (p = 0.03) but no difference in bilirubin levels between groups.

Immediate versus delayed umbilical cord clamping in premature neonates born < 35 weeks: a prospective, randomized, controlled study (11)

Randomized 60 infants to clamping at 5-10 seconds vs. 30-45 seconds.  Delayed clamping infants had higher BPs and hematocrits.  Infants < 1500 grams with delayed clamping needed less mechanical ventilation and surfactant.  Trend towards more polycythemia in delayed group, but not statistically significant.

And that’s just some of it.  I’ll be happy to send you an Endnote file with a pile more of you’d like it.  If the burden of proof is on us to prove that immediate clamping is good, that burden is clearly not met.  And furthermore, there is strong evidence that delaying clamping as little as 30 seconds has measurable benefits for the infant, especially in premature babies and babies born to iron deficient mothers.

So basically, we should be doing this.  I’m going to try to effect some change in my department, but there are a lot of things that need to happen for us to change as a general culture.  It can’t just be the OBs.  L and D nurses and pediatricians need to buy in as well.

Some people will argue that premature babies need to be brought to the warmer right away for resucitation.  I don’t know the answer to this, but it’s worth study.  One might think that it is important to intubate a very premature baby right away, but I have to wonder if that intact cord will be better at delivering oxygen to the baby for 30-60 seconds than the premature lungs.  Particularly in cases of fetal respiratory acidosis, there is strong logical argument that a baby might be better resuscitated by unwrapping the cord and letting it flow a bit than trying to oxygenate it through its lungs.  Until that placenta is detached, you have a natural ECMO system.  Why not use it?  Certainly there are exceptions to this logical argument, abruption being the biggest one, and perhaps even severe pre-eclampsia and other poor feto-maternal circulation states.

I wonder at times why delayed cord clamping has not become the standard already; why by and large we have not heeded the literature.  It is sad to say that I believe it is because the champions of this practice have not been doctors, but midwives, and sometimes we are influenced by prejudice.  Clearly, midwives and doctors tend to have some different ideas about how labor should be managed, but in the end data is data.  We championed evidence based medicine, but tend to ignore evidence when it comes from the wrong source, which is unfair.  It is fair to critique the research and the methods used to write it, but it shouldn’t matter who the author is.  In this case, Mercer and other midwives have done the world a favor by scientifically addressing this issue, and their data deserves serious consideration.

To quote Levy et al (12) “Although a tailored approach is required in the case of cord clamping, the balance of available data suggests that delayed cord clamping should be the method of choice.”  We ought to heed this advice better.   Like episiotomy, this change in practice may take awhile, but we should get it started.   I’m going to work on it myself.  How about you?

1.            Martin DL. The Protection of the Perineum by Episiotomy in Delivery at Term. Cal State J Med 1921 Jun;19(6):229-31.

2.            Barrett CW. Errors and evils of episiotomy. Am J Surg 1948 Sep;76(3):284.

3.            Rodriguez A, Arenas EA, Osorio AL, Mendez O, Zuleta JJ. Selective vs routine midline episiotomy for the prevention of third- or fourth-degree lacerations in nulliparous women. Am J Obstet Gynecol 2008 Mar;198(3):285 e1-4.

4.            Gossett DR, Su RD. Episiotomy practice in a community hospital setting. J Reprod Med 2008 Oct;53(10):803-8.

5.            Westfall R. An ethnographic account of lotus birth. Midwifery Today Int Midwife 2003 Summer(66):34-6.

6.            Weeks A. Umbilical cord clamping after birth. Bmj 2007 Aug 18;335(7615):312-3.

7.            Mercer JS, Vohr BR, McGrath MM, Padbury JF, Wallach M, Oh W. Delayed cord clamping in very preterm infants reduces the incidence of intraventricular hemorrhage and late-onset sepsis: a randomized, controlled trial. Pediatrics 2006 Apr;117(4):1235-42.

8.            Baenziger O, Stolkin F, Keel M, von Siebenthal K, Fauchere JC, Das Kundu S, et al. The influence of the timing of cord clamping on postnatal cerebral oxygenation in preterm neonates: a randomized, controlled trial. Pediatrics 2007 Mar;119(3):455-9.

9.            Chaparro CM, Neufeld LM, Tena Alavez G, Eguia-Liz Cedillo R, Dewey KG. Effect of timing of umbilical cord clamping on iron status in Mexican infants: a randomised controlled trial. Lancet 2006 Jun 17;367(9527):1997-2004.

10.            Strauss RG, Mock DM, Johnson KJ, Cress GA, Burmeister LF, Zimmerman MB, et al. A randomized clinical trial comparing immediate versus delayed clamping of the umbilical cord in preterm infants: short-term clinical and laboratory endpoints. Transfusion 2008 Apr;48(4):658-65.

11.            Kugelman A, Borenstein-Levin L, Riskin A, Chistyakov I, Ohel G, Gonen R, et al. Immediate versus delayed umbilical cord clamping in premature neonates born < 35 weeks: a prospective, randomized, controlled study. Am J Perinatol 2007 May;24(5):307-15.

12.            Levy T, Blickstein I. Timing of cord clamping revisited. J Perinat Med 2006;34(4):293-7.

But the world, at first, didn’t want to discuss it.   We immediately attacked the USPTF, even accusing them of somehow being in league with new health care reform policies meant to reduce costs, at the known expense of women’s lives.  Even Sanjay Gupta went attack dog against one of the USPTF members live on CNN.  That was the most surprising thing to me.

But now people are starting to come around, and they are coming around pretty much to where I started.

My initial reaction to the guidelines wasn’t so negative.  The USPTF aren’t a bunch of dummies.   They are educated people who looked at the situation from a epidemiological and mathematical point of view.   And from that point of view, their recommendations are sound.   People who argue that they don’t care about individual women fail to realize that they are asking for something that cannot be.  Epidemiology, almost by definition, ignores individuals. It is about large groups of people, and mathematically defining the interactions of various interventions on those groups.   It isn’t about individual people at all, and to think that epidemiologists should professionally care about individuals is to misunderstand their very nature.

We need epidemiologists, for the very reason that everybody attacked them.  They think about the large groups and ignore individuals, so that we doctors can think about individuals and ignore the large groups.  We need them so that we can think about our patients as infinitely important, because they think about the population as infinitely important.  We are Kirk.  They are Spock.

The fact that their analysis says that women 40-50 shouldn’t get mammograms doesn’t mean that doctors should completely stop ordering them.  It just means that on a population level, it doesn’t make sense.  That doesn’t mean that it is wrong for everyone under 50.  Their analysis just means that we need to think about it a little more.  We need to talk to our patients and explain that mammography in a low risk 40 year old woman has some downsides.  And then we let them decide.

I’ve been a little slow posting on this topic, because honestly I felt a little ignorant.  I was amazed that so many people felt so versed in the situation that they were able to condemn the USPTF’s recommendations so thoroughly, and so quickly.   I didn’t write anything because I just didn’t know yet.  I’m finally writing now because I finally understand just enough of it to say something that is worthwhile to me.  I still don’t get it all, but enough to write at least a few words.

Some other people have written some thoughtful posts as well, that are worth a read:

David Rind, “USPSTF, Mammography, and Grading Recommendations”

Medscape Review

Here is what is coming up -

11/27/09 -  Dr Paul Ridker – Massively published cardiologist from Brigham and Women’s, lead author for the 24 country JUPITER trial, examining the effects of crp on heart disease and efficacy of statins in non-hyperlipemic but crp high patients.  Will be talking about crp and heart diease in women, as well as the modern model for heart disease prevention and detection.  It ain’t all about lipids anymore folks!  This is just 2 days away so get me the questions quick!

TBA – Dr John Schnorr – Reproductive Endocrinologist from Southeastern Fertility – Specific topics to be finalized.  Dr Schnorr pioneered cryopreservation and restoration of ovarian tissue around the time of chemotherapy.

TBA – Dr Jennifer Gunter (@drjengunter) – Generalist OB/GYN and Reproductive Infectious Disease and vulvar disease specialist, also boarded in pain management (quad boarded!)  Will be talking about vulvar disease and her new book!

TBA – Dr Chukwuma Onyeije(@chukwumaonyeije) – MFM and Web 2.o afficionado in Atlanta, GA.  We’re going to talk about the new USPTF mammography guidelines, and the role of traditional and web media in the publics perceptions of these issues.  We’d love to have a third or fourth guest for a roundtable on this one (@drjengunter, @macobgyn, @somebodyelse?)

If you have any questions for these folks, leave them in the comments.  If you have ideas for people you would like to see in a podcast, or you want to be on the podcast yourself, let me know that too!  I’d love to have guests to talk about their research and work, or to just help me do one of the regular journal club review episodes!

Academic OB/GYN Episode 12 – Evidence Based Postpartum and Postoperative Instructions

I just don’t get it.  If a physician is going to take the time to create a blog to spread his or her opinions and expertise, why wouldn’t they do it under their own name?  In a way it really bothers me.   There is so much information on the web, and a great deal of it is poorly sourced and unreliable.  I would like to think that physicians will publish medical information that is accurate, at least as well as we know, and that the MD or PhD credential will lend credibility to their writings.   But to me it just destroys that credibility when the doc chooses to blog under a psuedonym.

I think that some docs are worried that their words will be used against them in a court of law.  I believe that people believe this, but I certainly don’t believe that myself.  Its just paranoia.  At some level that’s like thinking that there’s somebody listening to you, just dying to take you out of context and destroy you.  The problem with that thinking is that it ignores that the original source is always available for review later, and ultimately the blogger controls the context.  We have the ability to write whatever we want.  I’ll occasionally write something inflamatory, but I’ll stand by it as what I believe.  Whatever I write certainly reflects what I believe when I write it, but that doesn’t mean I don’t reserve the right to change my mind.  The idea that any idea I write down defines me forever more is just obtuse, and seems almost frightening to me, an affront to the potential for personal development.  Is every author defined by their first novel?  Is every musician defined by their first album?  I would hope that everybody matures with time, and doesn’t perpetually agree with every bit of material they ever produced.

More importantly, writing anonymously ignores the potential for branding oneself.  Every blogger has the opportunity to create their own brand, through all facets of social media.  Why would you want to brand a faceless image?   This is not V for Vendetta.  The ails of the medical system are not going to be cured by some faceless crusader and a bunch of bald headed rebels.   We need real faces with real names who can bring real arguments.  If I am trying to effect some real change, my credentials are a weapon to be used, and hell if I’m going hide them.   All medical professionals are respected members of society.  Hiding behind a mask undermines that respect, and in some ways hurts us all.

If the goal is to educate, the mask undermines that as well.  There are so many poor sources out there, and I have no interest in getting my education from a source that claims to be a physician but doesn’t want to tell me his or her name.

Sermo, the physician’s social network, gets around this somewhat by requiring that all registered users prove that they are licensed physicians.   But still the anonymity of it bothers me.  Over time I have gotten to know the more prevalent posters, but do I really know them?  I know that “OBGYNFlyer” is a strong surgeon who is pretty thoughtful, that “Andrea333″ is a psychiatrist that has no tolerance for anything remotely pro-choice, and that “steeldoc”, having been sued at least once, will do absolutely anything to avoid a repeat courtroom appearance.  But do I really know these people?   Ultimately these people are creating an image of themselves that may or may not be real, and there is no way for anyone to corroborate them at all.  Sermo doesn’t even require that MDs represent themselves in their actual specialties.  For all I know their characters could be complete fabrications.  It happens all over social media, so why not on Sermo?  And that bothers me.  In some cases certain screen names have been demonized, and others have been canonized.  One character eventually left because of all the abuse he/she got on the site.  Another character “wonposet” is held up as a near-deity.  But who really knows who these people are.  “wonposet” posts many beautiful and thoughtful posts, but who knows how much of that is really his/her character.  I’m sure he is a normal person, with light and dark parts, who chooses to only post the light.  Similarly some folks who seem to always post negatively are virtual pariahs, but in reality they are probably just getting their angst out a bit.

Those that post on Sermo under their real names are often criticized for somehow exposing themselves to dark forces of medical malpractice.   By now most OBGYNs on Sermo know that “markalanis” is a smart young MFM in Charleston, SC, “creasman” is William Creasman, and “nickfogelson” is a cocky young generalist with a blog.  If I get sued I’ll point to this blog entry as my defense.

So I encourage all you anonymous medbloggers out there to come out from under the sheets and reveal yourselves.  The biggest benefactor of this decision will be you.  Or at least comment on this blog and explain your motivation.

Somehow the world has gotten the idea that just because there is a lot of information available on the internet they now can become experts overnight.  The problem is that all the information in the world does not give someone the clinical judgement of a physician or other experienced practitioner, just as reading a manual on carpentry does not make you an experienced contractor.   Reading Harrison’s does not make you an internist.  Reading Gabbe does not make you an obstetrician.  It takes years of experience.

The reading is necessary but not sufficient.   It takes years of experience and training to get the clinical judgement necessary to use all the facts learned in those books effectively.  That is why we supervise residents for 3-8 years before we let them out on the world. Presumably they have already read the books before they start, but clearly they need those years before they really have the skills they need.

So check out Godin’s post, and some comments by 33 charts as well.  They’re worth the read.

Academic OB/GYN Episode 11 – Grey Journal October-November 2009

Apparently, this drug has been available in Europe for quite a long time, and there is substantial evidence of its efficacy and safety for treatment of a wide variety of bleeding issues, both gynecologic and otherwise.  Tranexamic acid (Wiki, WA) is in class of drugs called antifibrinolytics.   It is related to the drug Amicar (ε-aminocaproic acid) which is used in the US most notably after dental procedures as a mouthwash in patients with bleeding disorders.  These drugs function by blockade of lysine binding sites on plasminogen, thus blocking degradation of plasminogen into plasmin (sort of an anti-tPA).  Through this mechanism it stabilizes clots and prevents clot breakdown, thus augmenting the clotting system and decreasing bleeding.

Tranexamic acid has been studied in a wide variety of medical applications, all in situations where improved blood clotting is required.   Some studied applications include reduction of blood loss in CABG surgery, decreasing blood loss during and after cesarean delivery, and control of severe upper GI bleeding.

The use of tranexamic acid for control of mennoraghia has also been thoroughly studied, and based on the data already in press it appears to be effective in this use.

Here are a few studies that support the efficacy of the drug:

Gultekin et al did a study of 132 women who presented to the hospital with disfunctional uterine bleeding who were put on 500 mg of tranexamic acid.   Patients were used as their own control group, comparing pre-treatment labs and history with post treatment labs and history.  On treatment, bleeding days decreased from a median 9 days to 5 days, and median hemoglobins rose from 10.6 to 12.1. 66% of patients required no other treatment.  The study’s major methodologic concern is that the pretreatment control is affected by recall bias in comparison to contemporaneously gathered treatment arm data.

Senthong et al conducted a randomized trial of tranexamic acid for women who had problematic bleeding while on DMPA.   88% of the women in the treatment arm had cessation of bleeding by 4 weeks, against only 8% in the placebo arm.  Four weeks after cessation of treatment, the treatment arm still had better bleeding profiles than the placebo arm, with 68% having bleeding free intervals of > 20 days vs 0% with the nontreatment arm.

Wellington et al reviewed the use of tranexamic acid, with favorable results: “In a number of small clinical studies in women with idiopathic menorrhagia, tranexamic acid 2-4.5 g/day for 4-7 days reduced menstrual blood loss by 34-59% over 2-3 cycles, significantly more so than placebo, mefenamic acid, flurbiprofen, etamsylate and oral luteal phase norethisterone at clinically relevant dosages. Intrauterine administration of levonorgestrel 20 microg/day, however, produced the greatest reduction (96% after 12 months) in blood loss; 44% of patients treated with levonorgestrel developed amenorrhoea. Tranexamic acid 1.5 g three times daily for 5 days also significantly reduced menstrual blood loss in women with intrauterine contraceptive device-associated menorrhagia compared with diclofenac sodium (150 mg in three divided doses on day 1 followed by 25 mg three times daily on days 2-5) or placebo…. tranexamic acid may be considered as a first-line treatment for the initial management of idiopathic menorrhagia, especially for patients in whom hormonal treatment is either not recommended or not wanted.”

A Cochrane review addressed tranexamic acid in meta-analysis for heavy menstrual bleeding, and found it effective in reducing blood loss.  “Antifibrinolytic therapy compared to placebo showed a significant reduction in mean blood loss (WMD -94.0 [-151.4, -36.5]) and significant change in mean reduction of blood loss (WMD -110.2 [-146.5, -73.8]).”

So overall, there appears to be strong evidence of efficacy of the drug.  The only catch for me is that as a competitive inhibitor of plasminogen activity, it acts as a pro-coagulant and potentially increases the risk of thrombotic event.   There are a number of case reports of unusual thrombosis (CVA in a 28 year old woman, recurrent pulmonary embolism in another woman), but there is a no clear increased risk of thrombosis described in the larger studies.  Most likely this drug does increase the risk of thrombosis a small amount, and this is likely affected by host genetic factors as well.  The alternatives also increase thrombotic risk somewhat (OCPs predominantly), though a Mirena IUD is able to achieve the same effect without the thrombotic risk.

For me, I will consider the use of this drug in my patients with mennorhagia, but will hold off on anybody with a defined thrombotic risk.  My use will also be very dependent on the cost of the drug.  I cannot see using this drug at this time if it costs $100 a month or is not being adequately covered by insurers.

Any thoughts from the viewers?

Sources:

Role of a non-hormonal oral anti-fibrinolytic hemostatic agent (tranexamic acid) for management of patients with dysfunctional uterine bleeding.  Gultekin M, Diribas, K, Buru E,Gökçeoğlu MA. Clin Exp Obstet Gynecol. 2009;36(3):163-5.

Antifibrinolytics for heavy menstrual bleeding.  Lethaby A, Farquhar C, Cooke I. Cochrane Database Syst Rev. 2000;(4):CD000249.

Tranexamic acid: a review of its use in the management of menorrhagia. Wellington K, Wagstaff AJ. Drugs. 2003;63(13):1417-33.

The effect of tranexamic acid for treatment of irregular uterine bleeding secondary to DMPA use.  Senthong AJ, Taneepanichskul S. J Med Assoc Thai. 2009 Apr;92(4):461-5.

The risk of venous thromboembolism associated with the use of tranexamic acid and other drugs use to treat menorrhagia: a case-control study using the General Practice Research Database.  Sundstrom A, Seaman H, KielerH, Alfredsson L. BJOG. 2009 Jan;116(1):91-7. Epub 2008 Nov 11.

The same thought has carried on to our management of the second stage.  Early in my internship I was taught that if a primiparous woman with an epidural was not delivered after three hours of second stage labor, it was time for forceps or a cesarean section, and we did a lot of these as well.  Some of these babies were massive, and the cesarean in those cases felt righteous.  Nothing was more relieving than pulling out a ten or eleven pound baby from a hysterotomy.  A shared smile between residents and a nod from the attending “that one wasn’t coming out from below!”  But sometimes the baby was only 7 pounds, and one had to wonder if you could say the same.   Was that average sized baby that wasn’t delivering really destined to die in there?  Seemed unlikely.

Added on to all this was the apparent truth that cesareans for arrest were not distributed equally across 24 hours of the day.  In fact, there were two prime times – late afternoon and around 4-5 AM: the few hours before the morning and afternoon board checkouts.  Nobody wanted to leave this inevitable cesarean for the next team.  Later in practice I saw these concerns coming into play even more among private practitioners who did not have the luxury of waiting for an unlikely vaginal delivery, being pressured by their full offices or waiting families.  As was demonstrated by Steven Leavitt in Freakonomics, humans respond to incentives.  And there are plenty of non-medical incentives to cut.

In my first position after residency at the University of Hawai’i, I saw a lot of women given a lot more time to deliver that Friedman would have recommended, and I saw that a lot of them delivered.   Perhaps due to cultural differences, or perhaps because the patient to resident ratio precluded close following of every low risk mother, people weren’t in such a hurry to deliver protracted patients.   And remarkably, a lot of mothers delivered that might have been cut where I had trained.  But perhaps it was the population: wide pelviced Polynesians rather than African Americans, and fewer teenage mothers.  It certainly played a part: after a few years I stopped being amazed at the ease at which a Samoan mother would deliver a ten or eleven pounder.  The idea of pre-emptive section for macrosomia seemed almost ridiculous.

And so, I have many questions about this, none of which I have answers for.   Was Friedman just wrong?   Does his curve describe something that just doesn’t exist anymore?  To be sure, the population he studied is not who we are caring for now.   His population was primarily women without epidurals who entered active labor.   We now use epidurals in the majority of labors, and labor induction is quite common, perhaps even the rule in some practices.  And given the large effect of genetics I saw in just two different places, can we really extrapolate Friedman’s data to all women?  And what about people who labor outside of the hospital?  What percent of them meet the definition of arrest yet go on to deliver, blissfully ignorant of their temporary fetal impaction.

Clearly, I don’t have answers to all of this, but it does make me think – and it has changed my practice.   I residency I pretty much cut when people hit two hours of arrest, and either pulled or cut at three hours of second stage.   These days, I wait it out, particularly if the strip looks good.   And I almost never cut a multiparous woman for arrest.  It just is too bizarre to me that a woman who did it before wouldn’t be able to do it again.

My biggest problem with all this is the question of what I should be teaching my residents.  Friedman’s curve is easy to teach, because it is objective.  The problem is that it may not be right.  But can I teach that it is wrong? And if so, what should I replace it with?  I don’t know.  For now I try to model benign neglect of putatively arrested women with reassuring fetal heart rate tracings…. at least until board checkout.

“A patient of mine had ovarian cancer, she’s brought her 13 year old in for a consultation regarding various issues of irregular menses. ….how soon we should start getting CA125s…. Have an answer/opinion for exactly how young to start?”

That’s a great question!

First, there is probably not a definitive answer.  Screening for ovarian cancer is clearly an area where we do not have good answers.  I think a clear part of this question is actually whether or not the patient should be screened at all.  Patients think that there should be a good screening for ovarian cancer, but based on current literature and practice, I don’t think there is any method for screening this patient that is effective.

Per American Cancer Society as of 8/27/09:

“The problem with this test is that conditions other than cancer can also cause high levels of CA-125. In addition, someone with ovarian cancer can still have a normal CA-125 level. When a CA-125 level is abnormal, many doctors will repeat the test (to make sure the result is correct). The doctor may also consider ordering a transvaginal ultrasound test. In studies of women at average risk of ovarian cancer, these screening tests did not lower the number of deaths caused by ovarian cancer. This is why transvaginal sonography and the CA-125 blood test are not recommended for ovarian cancer screening of women without known strong risk factors. Even when these tests are used in women at high risk, it is not known how helpful they are.” (http://bit.ly/mayII)

I think the issue with screening this patient is that there are so many reasons a young person could have a positive CA125, it is unclear what one would do with the result.  Some have suggested that one could get serial CA125 tests and look for an escalating level, which would make sense, though I don’t believe this has been evaluated prospectively.

Several studies have shown CA125 screening to be ineffective even in BRCA+ positive women, even in combination with serial transvaginal scanning.  These patients have as high as 50% chance of getting ovarian cancer, while the patient you describe (assuming no other family history) has only a 5% lifetime risk.

Stirling et al “Annual surveillance by transvaginal ultrasound scanning and serum CA-125 measurement in women at increased familial risk of ovarian cancer is ineffective in detecting tumors at a sufficiently early stage to influence prognosis.”

Olivier et al “By combining CA125 with TVU results, a PPV of 40% was achieved. However, the diagnostic tools appear to be only sensitive in detecting ovarian cancer at an advanced stage, while three of four tumors with early-stage disease in this series had normal screening tests prior to the diagnosis.”

That being said, there are a few studies that have shown some more promising results…

Tailor et al “Transvaginal sonography can effectively detect intraovarian cancer and tumors of borderline malignancy in women with a family history of the disease. Screening efficacy is related to the type of family history.”

I think the best answer is that there is no clear benefit to screening this patient.   It would be worthwhile to get BRCA testing on the mother, which if positive, would have clear implications for the daughter.  If the daughter were BRCA positive she would be candidate for prophylactic oopherectomy after she completes childbearing.  A genetic counseling visit for the mother and daughter would be appropriate, and can help guide decision making.   New information is coming out all the time on this topic, and genetic counselors are often very up to date.  Your referral gyn/oncologist may also have a good opinion.

She also can reduce her lifetime risk of ovarian cancer by using birth control pills except when she desires pregnancy.  If she is strongly interested in screening, there may be a screening research protocol ongoing at a nearby academic center.

Sources:

Screening for familial ovarian cancer: failure of current protocols to detect ovarian cancer at an early stage according to international Federation of Gynecolgoy and Obstetrics System.Stirling D, Evans DG, et al.  J Clin Oncol. 2005 Aug 20;23(24):5588-96.

Screening for familial ovarian cancer: poor survival of BRCA 1/2 related cancers. Evans DG, Gaarenstroom KN et al. J Med Genet. 2009 Sep;46(9):593-7. Epub 2008 Apr 15.

CA125 and transvaginal ultrasound monitoring in high-risk women cannot prevent the diagnosis of advanced ovarian cancer. Olivier RI, Lubsen-Brandsma MA. Gynecol Oncol. 2006 Jan;100(1):20-6. Epub 2005 Sep 26.

Results from an ultrasound-based familial ovarian cancer screening clinic: a 10-year observational study. Tailor A, Bourne TH et al.  Ultrasound Obstet Gynecol. 2003 Apr;21(4):378-85.

Thanks for the question!  Hope that helps a bit

Nicholas Fogelson, MD

This thing is growing folks, and you can help.

Every time an Academic OB/GYN viewer asks a question, a blog post gets its wings…..

email@academicobgyn.com

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Academic OB/GYN Episode 10 – Green Journal October 2009

I have been aware that some of the podcast episodes did not have great audio quality.  This was all  my fault, not being an audio engineer and lacking experience with this.

Over time I have learned how to do this stuff better, and audio quality in the podcasts has improved in general, and should continue to improve.

I have gone back through the old podcasts, and in most cases have substantially improved their audio quality, including increasing volume on the ones that were too quiet (including the recent Episode 7 which was way too quiet.)   So if you downloaded them before and chose not to listen because of objectionable audio quality, I invite you to delete what you have and redownload the improved versions.  The content is great and worth listening to!

Thanks!

Nicholas Fogelson, MD

Academic OB/GYN

PS. Episode 3, it seems, is beyond repair.  But Dr Robinson is still worth listening to if you can stand the static.

“She’s only 19 weeks, they don’t fern this early.”

“There’s blood in the sample, that makes it not fern.”

“She has chorio, that makes it not fern.”

Over the years, this has driven me a bit crazy, because the real reason that the slide is not ferned is not any of these reasons.  The reason there is no fern on the slide is because the fluid on the slide is not amniotic fluid.

Clearly there are some reasonable questions to be asked about what will cause or prevent ferning in a vaginal pool sample.   Does gestational age affect it?  Does blood affect it?   How long does one need to wait?

Asking these questions is great.  What is not great is making crap up about the answers when these questions have been clearly answered in the literature.

Ferning of amniotic fluid contaminated with blood.  Rosemond RL, Lombardi SJ, Boehm FH. Obstet Gynecol. 1990 Mar;75(3):338-40.

“Amniotic fluid was obtained from 38 patients between 16-38 weeks’ gestational age who underwent amniocentesis. Amniotic fluid was immediately mixed with freshly obtained, heparinized fetal cord blood in varying concentrations (blood to amniotic fluid 1:5, 1:10, 1:20). The slides were examined microscopically for the presence of ferning. All samples were fern-positive, but many had atypical ferns described as “skeletonized.” As the concentration of blood to amniotic fluid increased, the number of atypical ferns increased (32 of 38 at 1:5, 22 of 38 at 1:10, and nine of 38 at 1:20). We conclude that the presence of blood may alter the morphology of the fern, but does not act as a contaminant that would affect the accuracy of the test.”

Amniotic fluid arborization: effect of blood, meconium, and pH alterations. Reece EA, Chervenak FA, Moya FR, Hobbins JC.. Obstet Gynecol 1984 Aug;64(2):248-50

“Thirty-six specimens of amniotic fluid across gestational ages (16 to 42 weeks) were tested. The fern test was unaffected by meconium at any concentration and by blood at dilutions of 1:10 or greater. When blood and amniotic fluid were mixed in equal amounts, ferning was not present. Arborization of amniotic fluid was unaffected by pH alterations.”

The ferning and nitrazine tests of amniotic fluid between 12 and 41 weeks gestation.  Bennett SL, Cullen JB, Sherer DM, Woods JR Jr.  Am J Perinatol. 1993 Mar;10(2):101-4

“Samples were obtained from amniocenteses between 14 and 42 weeks. Part I: Of 112 samples allowed to dry on a slide for 3 minutes only, 86.6% were ferning positive and 100% were nitrazine positive. Flame-drying increased the presence of ferning to 96.4%. Part II: 363 samples were allowed to dry completely for up to 10 minutes. All samples were ferning and nitrazine positive….These tests may be reliably performed at gestations of 12 to 41 weeks.”

MORAL:  Amniotic fluid will fern at any gestational age, in varying pH, and in the presence of a moderate amount of blood.  If you have fluid on the slide, and the slide doesn’t fern, you need to seriously doubt the diagnosis of ruptured membranes.

Academic OB/GYN Episode 9 – Web 2.0 and YOU!

Academic OB/GYN is sponsored by Due Dater, iPhone and iPod Touch software for calculating gestational ages and due dates for obstetrics professionals.  Available at the Apple App Store.

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:

Pharmacokinetics of repeated doses of misoprostol.  Tang OS, Schweer H, Lee SW, Ho PC. Hum Reprod. 2009 Aug;24(8):1862-9. Epub 2009 Apr 23.

Misoprostol: pharmacokinetic profiles, effects on the uterus and side-effects. Tang OS, Gemzell-Danielsson K, Ho PC.  Int J Gynaecol Obstet. 2007 Dec;99 Suppl 2:S160-7.

The optimization of intravaginal misoprostol dosing schedules in second-trimester pregnancy termination.  Dickinson JE, Evans SF. Am J Obstet Gynecol. 2002 Mar; 186(3):470-4.

Academic OB/GYN Episode 8 – Grey Journal September 2009

This episode is sponsored by Hooah! Software and their iPhone program Due Dater, a gestational wheel and calculator for obstetric professionals.

Oral Contraceptive effectiveness according to body mass index, weight, age, and other factors by Dinger et al.

I thought been pretty well established that oral birth control pills have somewhat lower effectiveness in patients with higher BMIs (30+), and then this study comes around and throws a wrench in the works:  In 112,659 women years of exposure and 545 unplanned pregnancies, there was no statistical association between patient BMI and contraception failure.

An unexpected result, for certain.  So here’s how they studied the questionThis study is a  secondary analysis of the EURAS-OC study, a large European prospective cohort study intended to investigate the potential association between the new progestin drosperinone and cardiovascular events, created by Bayer at the demands of European drug authorities.  This study created a huge dataset of women on oral contraceptives, including demographic data and long term clinical outcomes.  In order to investigate the effects of BMI on contraceptive failures, our compared rates of unintended pregnancy in different groups of women within the EURAS-OC study.  Given the large dataset, the authors were able to stratify risk of unintended pregnancy not only by BMI, but also by progestin.

After data analysis, overall failure rates were strikingly low – Year 1 failure rate was 0.75%, year 2 1.33%, year 3 1.53%, and year 4 1.67%.  Furthermore, for all progestins except for chlormadinone (which is not available in the US), there was no association between BMI and failure rate.    With chlormadinone there was a 3x risk of failure rate at BMI > 30, which is thought to be due to the highly lipophilic nature of that particular progestin, and thus a higher relative volume of distribution compared to other progestins.

So why is that all worth talking about?  – Its because this data is just so different that what we have seen before -

Holt et al Green Journal 2005 – case control of unintended pregnancies on OCPs, odds ratio of failure 1.58 – 2.22 for BMIs > 27, depending on level of obesity and consistency of OCP use.

Brunner  et al Ann Epidemiol 2006 – case control of unintended pregnancies on OCPs in South Carolina, odds ratio of failure  2.54 – 2.82 for obese women.

Brunner et al Matern Child Health 2005 – retrospective cohort of 18,445 women, adjusted OR for unintended pregnancy in obese women 1.73 – 1.75.

Furthermore, the overall failure rate of around 1% is much different than the 9% first  year failure rate reported in the last iteration of the US National Survey of Family Growth.

When we see such different results of studies that seem to ask the same question, one of the following must be true: 1) One of the studies is biased, or both are 2) The studies are looking at different populations or 3) The studies may be defining their outcomes differently.   In this case, I think all three are happening.

The biggest difference that I see between this study and the American studies is the way patients were recruited, and think this difference could have a strong effect on the outcomes.   This study was a prospective cohort with data gathered over many years.  Each patient studied was approached after they had decided to use OCPs.  If they decided to enter the study, they were closely monitored for years for a large number of outcomes, and had medication compliance frequently measured.   The American studies were either case control studies looking at contraceptive failures compared to matched controls, or in the case of the second Brunner study, a retrospectively constructed cohort.  So why does this matter?  It goes back to an old engineering saying: Anything you measure you will improve.  The patients in the European study knew they were in a study, and that they would be asked to report their OCP compliance, making them more likely to be compliant with medications than someone who does not know their outcomes would be analyzed.   2 American case control studies suggested that the effects of obesity on pill efficacy is pronounced in women who are not consistent with their pills.   As such, it is possible that this huge study misses the real life effect of obesity by producing a preposterous population of peristently perfect pill popping patients!

Another difference between the European study and the previous American data is the type of obesity seen in the study populations.   Unfortunately for America, we have a lot more obesity than Europe.  This study had a mean BMI of around 22, and sadly the current mean BMI in the United States is 26.4. This translates to a larger number of superobese ( > 35 ) in American study populations, which are not as well addressed in this large data set composed of less obese people.

Finally, overall failure rate is calculated much differently in the European study that in the large American population studies.  In the American studies women-years are counted in month by month increments, but only when women are sexually active.  The European study counts a woman-month irrespective of whether or not the woman has had sex in that month.  It is arguable which of these methods is more appropriate, but inarguable that it has a profound effect on the absolute value of the failure rate.  As we (the Americans) are counting months only when there is intercourse during the month, there will assuredly be a higher failure rates than if we excluded the non-exposed months, which increase the denominator(exposure) without possibly increasing the numerator(failures.)  As such, the overall failure rate of around 1% is difficult in this study is hard to compare to the American failure rate of 9%, as it could represent decreased sexual activity in Europe relative to America as much as it could represent different contraceptive efficacy.

So what do we take from all this?    I think this new study shows us that if people are highly compliant with OCPs, failure rates are very low and are not strongly affected by BMI – but given the potential biases created by study design and interpretation, I’m not ready to say that OCPs work just as well in obese and superobese women as they do in lower BMI women.

So what do you think?

Article:

Dinger JC, Cronin M, Möhner S, Schellschmidt I, Minh TD, Westhoff C. Oral contraceptive effectiveness according to body mass index, weight, age, and other factors.  Am J Obstet Gynecol. 2009 Sep;201(3):263.e1-9. Epub 2009 May 30.

• Pregnant women because they are at higher risk of complications and can potentially provide protection to infants who cannot be vaccinated;
• Household contacts and caregivers for children younger than 6 months of age because younger infants are at higher risk of influenza-related complications and cannot be vaccinated. Vaccination of those in close contact with infants younger than 6 months old might help protect infants by “cocooning” them from the virus;
• Healthcare and emergency medical services personnel because infections among healthcare workers have been reported and this can be a potential source of infection for vulnerable patients. Also, increased absenteeism in this population could reduce healthcare system capacity;
• All people from 6 months through 24 years of age
  • Children from 6 months through 18 years of age because cases of 2009 H1N1 influenza have been seen in children who are in close contact with each other in school and day care settings, which increases the likelihood of disease spread, and
  • Young adults 19 through 24 years of age because many cases of 2009 H1N1 influenza have been seen in these healthy young adults and they often live, work, and study in close proximity, and they are a frequently mobile population; and,
• Persons aged 25 through 64 years who have health conditions associated with higher risk of medical complications from influenza.

If initial supplies are inadequate to immunize all the patients in the above group, the following groups should have first access to vaccine:

• pregnant women,
• people who live with or care for children younger than 6 months of age,
• health care and emergency medical services personnel with direct patient contact,
• children 6 months through 4 years of age, and
• children 5 through 18 years of age who have chronic medical conditions.

Once the highest risk people are immunized, recommendations will likely grow to include all people 25 to 64, and finally to people 65+.   Unlike seasonal flu, Novel H1N1 (pandemic flu / swine flu) is actually less likely to strike older patients due to their likelihood to having been exposed earlier in their life (last outbreak of a related strain was 1974!)

It should also be noted that while many strains of seasonal flu are resistant to oseltamavir (Tamiflu), Novel H1N1 (Swine Flu) is typically  oseltamavir sensitive.   Patients or providers exposed to H1N1 patients may benefit from post exposure prophylaxis with Tamiflu.  Articles are being published weekly on new resistance in both Novel H1N1 and Seasonal Influenza A H1N1 and H3N2.   Check the CDC website for the most up to date information!

Source:

CDC  2009 H1N1 Vaccination Recommendations, updated July 29, 2009

Three articles will be published, two on the ability of various dosages of the vaccine to create an immune response, and a third on the presence of immune antibodies in people exposed to previous seasonal flu vaccines, and to past outbreaks of natural H1N1 “swine” flu.

The bottom line:

1) A single 15 microgram dose of the novel H1N1 vaccine creates an adequate immune response in near 100% of people within 14 days of administration.  There will be no need to have a second shot.   CDC guidelines will likely be changed to reflect this.

2) People who were immunized to the seasonal flu last year in the Northern Hemisphere have no or low chance of having immunity to Novel H1N1 (swine) flu.   People who were immunized with the southern hemisphere vaccine last year have some chance of immunity, but still should get the new vaccine this year.

3) People who were exposed to previous pandemic flu strains often have resistance to this pandemic flu.   Today’s novel H1N1 pandemic flu strain is likely related to the flu strains that caused outbreaks in 1918 and 1976.  Older patients are more likely to have been exposed to one of these outbreaks and be immune today.   Still, there are enough people in that age group that are not immune (higher than 50% in many cases) that all people should be immunized if possible.

Sources:

Response after One Dose of a Monovalent Influenza A (H1N1) 2009 Vaccine — Preliminary Report.  Greenberg ME, Lai MH, Hartel GF, Wichems CH, Gittleson C, Bennet J, Dawson G, Hu W, Leggio C, Washington D, Basser RL.N Engl J Med.  2009 Sep 10.

Trial of Influenza A (H1N1) 2009 Monovalent MF59-Adjuvanted Vaccine — Preliminary Report.  Clark TW, Pareek M, Hoschler K, Dillon H, Nicholson KG, Groth N, Stephenson I.  N Engl J Med. 2009 Sep 10.

Cross-Reactive Antibody Responses to the 2009 Pandemic H1N1 Influenza Virus.  Hancock K, Veguilla V, Lu X, Zhong W, Butler EN, Sun H, Liu F, Dong L, Devos JR, Gargiullo PM, Brammer TL, Cox NJ, Tumpey TM, Katz JM. N Engl J Med. 2009 Sep 10.

This episode is sponsored by Hooah! Software and their iPhone program Due Dater, a gestational wheel and calculator for obstetric professionals.

Academic OB/GYN Episode 7 – Green Journal September 2009