Episode 7.8 Osteopenia treatments, antenatal steroids, IOL methods, VBAC risk factors, and surgical hemostasis
In this episode, we discuss the latest recommendations for treatments for osteopenia and osteoporosis, including vitamin D and calcium, as well as bisphophonates and other medications.
Then we discuss new literature about best methods for induction of labor and risks factors for uterine rupture during a trial of labor after Cesarean. We also discuss a new trial about late preterm antenatal steroids.
Also we talk about a new article about mammalian menopause the evolutionary rolls of menopause and concealed ovulation (fun people, we know!)
Finally, we answer a listener question about bleeding during surgery.
00:00:02 Treatment of Osteopenia and Osteoporosis
00:14:40 Vaginal Birth After Cesarean Recommendations
00:24:05 Effectiveness of Late Preterm Steroids
00:35:49 Menopause and Evolution in Mammals
00:41:05 Concealed Estrus and Weight Gain Recommendations
00:47:56 Managing Surgical Hemostasis and Bleeding
Links Discussed
Antenatal Betamethasone for Women at Risk for Late Preterm Delivery
Most mammals go through the menopause – if they live long enough
The evolution of menopause in toothed whales
The association between indications for cesarean delivery and surgery time
Use of electrocautery for coagulation and wound complications in Caesarean sections
The fifteen minute cesarean delivery
Transcript
Announcer: 0:02
This is Thinking About OB-GYN with your hosts Antonia Roberts and Howard Herrell.
Howard: 0:17
Antonia.
Antonia: 0:18
Howard.
Howard: 0:19
What are we thinking about on today’s episode?
Antonia: 0:21
Well, we’re covering a bit of a potpourri of new studies today, including one about whales, and we also have a listener question First what’s a thing we do without evidence?
Howard: 0:33
Whales like water whales or the animal.
Antonia: 0:35
Yeah, like blue whales or like another kind of whales too, like the big animal in the sea.
Howard: 0:40
Yeah All right Well, a thing we do without evidence. How about treating osteopenia with pharmacologic interventions or continuing those drugs for longer than five years when they are used?
Antonia: 0:50
Okay, yeah, sure. So patients are recommended to start routine bone mineral density scans at a certain age I believe it’s 65, and possibly earlier if they have certain risk factors for osteoporosis, and that determination alone may be a bit more of a judgment call in some cases. But either way, if you get their DEXA scan or whatever other type of bone density scan and they’re diagnosed with osteopenia, they are likely going to be told to take some extra vitamin D and calcium, which could potentially be appropriate for them, but many of them will also be started on a bisphosphonate for that diagnosis. And osteopenia is kind of like pre-osteoporosis, if you want to think about it as if it were a progressive continuum. But what does the evidence say about this?
Howard: 1:40
Well, I think this is going to be an example of therapeutic drift. So while bisphosphonate therapy is fantastic for patients with osteoporosis and can prevent up to half of the fractures that occur in those patients, that doesn’t necessarily mean that it helps patients with osteopenia. And this is that hard thing of finding the inflection point where something’s useful and where it isn’t, and we have to draw a line somewhere, and we’ve historically drawn a line between osteopenia and osteoporosis. Now there was actually a new guideline from the American College of Physicians in 2023 that replaced the 2017 guideline, and neither of these guidelines recommend that patients with a diagnosis of just osteopenia receive bisphosphonate therapy. So in this new guideline published in the Annals of Internal Medicine in 2023 in January, they discussed specifically a large randomized controlled trial of zolendronate versus placebo in women over the age of 65 with osteopenia.
Howard: 2:31
Some of the patients in the study also had osteoporosis and some of the patients in the study had had prior fracture, so it was a mixed group. But this trial showed that some patients did indeed benefit in terms of reduced fracture risk, but most of those were again either patients with prior fracture or those with documented osteoporosis as opposed to osteopenia. But for patients with just osteopenia, there was no difference in the rate of hip fracture after three years and the rate of vertebral fracture did appear to be lower. But the study was insufficient to calculate an absolute risk reduction for patients with osteopenia alone. So for those patients no treatments were significantly found to reduce hip fracture.
Howard: 3:09
The bisphosphonates may be able to reduce fractures in osteopenic patients who’ve had prior fractures, however. So another way to say this is patients with a high FRAC score, which is another way of categorizing this. So there’s some gray area about those patients. But if you have an osteopenic patient who’s had a prior fracture, who has a high FRAC score, then you might consider bisphosphonate therapy. But even then, remember, that’s a gray area and for just simple osteopenia there’s no evidence that it’s effective.
Antonia: 3:36
Okay, got it. So what about vitamin D and calcium for those patients? I’ve seen some back and forth about this over the years. I think calcium used to be almost universal, but then it came out that it was associated with an increased cardiac risk, and so since then I’ve taken more of a backseat. And then the vitamin D hasn’t panned out either, at least for prevention of fracture or prevention of osteoporosis, although that one I still see prescribed to pretty much everyone all the time. So what does the evidence say?
Howard: 4:12
Well sure, and there’s potentially other negatives of taking calcium, as well as the cardiac risk. So the risk of kidney stones, for example, is increased when women supplement with additional calcium, and when you take 2,000 milligrams a day, which is typically the 1,000 milligram supplement on top of the average dietary intake, then there does appear to be increased cardiovascular risk.
Howard: 4:34
So the data is mixed though it looks like, due to the risks of calcium, that women who have 1,200 milligrams or so of calcium intake should not take any more than that, and in observational trials, most women in the United States get about that much in their dietary intake, so you really should only recommend calcium to women who have some reason, in particular, to have low dietary calcium.
Howard: 4:55
Now, vitamin D and calcium are both necessary for normal bone health and bone formation, but multiple trials at this point have shown that vitamin D supplementation is not effective at reducing the risks of osteopenia or osteoporosis.
Howard: 5:08
In fact, the US Permanent Services Task Force concludes against recommending supplemental vitamin D for this purpose at least. There might be a patient with severe vitamin D nutritional deficiency, but that should be relatively rare and most patients shouldn’t be recommended to take either vitamin D or calcium supplementation as part of a general health visit. There was also a trial published in 2022 called the VITAL vitamin D trial that included women over the age of 55. And this was a placebo trial that compared placebo versus vitamin D3 supplementation, and they found no difference in total fractures, non-vertebral fractures or hip fractures. They even found that there was no fracture reduction in people who had a history of a fragility fracture or who started out with a documented low baseline vitamin D level. That study was published in the New England Journal of Medicine in 2022, and I think that pretty much is the end of vitamin D for osteopenia, osteoporosis.
Antonia: 6:01
Okay, and that lack of benefit of vitamin D is true both for osteopenia and for osteoporosis. Okay, and that lack of benefit of vitamin D is true both for osteopenia and for osteoporosis. So now, what about treating osteoporosis, if they actually got that diagnosis? The pharmaceutical companies, I think, are pushing some more novel drugs these days, instead of the bisphosphonates that have been around for a while and that also already come in various preparations that can make them more tolerable.
Howard: 6:27
Well, from that same American College of Physicians guideline. Their recommendations are that we use bisphosphonates as the initial treatment to reduce fracture risk in any woman with osteoporosis and that we limit the use of prolia or denosumab as a second-line agent for those women who have a contraindication or have had adverse effects with bisphosphonate therapy.
Antonia: 6:49
Okay, so let’s talk about those newer drugs just for a moment. So the one is Prolia and the other one is Exgeva, I think, and their prices range from about $1,700 to over $3,000 per dose. A year’s supply would be two doses, so it’s once every six months, and by comparison, generic alendronate is available for usually less than $25 a month. So it is an expensive choice to switch from the alendronate to one of those newer ones, and there is also a one-year dosing interval. Injection of zoledronic acid, which is another bisphosphonate to limit the side effects of using the oral bisphosphonate. That one is called Reclassed and that’s about $1,250 per year, so still as much as one-fifth of the price of using one of those newer products, that denosumab, for example, and still also gets rid of most of the side effects of the oral bisphosphonate, which itself is of course, much cheaper than Prolia.
Howard: 7:57
Yeah, the pricing here is a huge deal and of course Prolia and those medications are being heavily promoted by the pharmaceutical industry. The definition of intolerance or a side effect of bisphosphonate therapy can get pretty broad, so patients get switched over for sometimes very minor or even unrelated symptoms that the drug reps suggest you look for. Some doctors may not even try bisphosphonate therapy anymore. They’ll just go straight to Prolia because it’s being sold to them anymore. They’ll just go straight to Prolia because it’s being sold to them. But the guideline clearly states that there should be a documented and significant adverse effect to bisphosphonates before making this switch. And of course that’s why you might consider the reclass injection once a year, which, yes, is expensive but of course a lot cheaper than Prolia.
Antonia: 8:38
And it’s a lot more convenient because it’s only once a year instead of twice. So I think the other thing you mentioned was continuing the bisphosphonate therapy for too long.
Howard: 8:48
Yeah, I see a lot of patients who’ve just been on this medication forever. So often somebody will just keep hitting refill and when they come in for their yearly visit, and before you know it, they’ve been on it for eight years or 10 or 12 years. But in almost all cases, the risks outweigh the benefits of continuing therapy after five years, and so if you’re going to continue it beyond five years link to the North American Menopause Society statement about these same issues it’s from 2021. So long ago.
Antonia: 9:41
So long ago. So it doesn’t have maybe some of the newer vitamin studies, but overall it’s still, I’d say, current.
Howard: 9:48
And it has a lot of the other stuff we didn’t talk about in regards to that.
Antonia: 9:51
So Okay, yeah, so okay, let’s get into our topics and review some recent current articles. We haven’t done a whole lot of new pieces of literature recently, so we’ll see how many we can get. Today there is a second volume of the Gray Journal’s Labor and Delivery Special Edition Supplement, and we did some articles from their first volume, I think even over last summer, so we’ll try to look through a few of those quickly as well. A lot of them are review articles. It’s a really big edition and it’s pretty interesting. One of them that I saw was a systematic review of methods of induction, and they concluded, in an article by Luis Sanchez Ramos and colleagues, that a single balloon catheter with concomitant vaginal misoprostol was the most effective method of labor induction.
Howard: 10:43
So isn’t that nice, well this is hard because there’s just a lack of head-to-head trials about of labor induction. So isn’t that nice? Well, this is hard because there’s just a lack of head-to-head trials about methods of induction. And so saying what the most definitive and effective way to induce labor is a tough thing to do. But, in fairness, if you’ve been following a lot of the recent studies that have come out in the last five to 10 years about labor induction methods, then this is probably the conclusion you would come away with.
Howard: 11:07
We know that the double balloon catheters aren’t any better than single balloon catheters and are just more expensive and we’ve talked about that before and we know that the combination of a catheter plus either oxytocin or misoprostol is probably the best methodology.
Howard: 11:22
So this is a very detailed systematic review and you can see all the recent literature that’s been published about this subject. And, of course, importantly, it also showed that the method of a Foley catheter or a single balloon catheter in misoprostol was not only associated with quicker delivery and a lower cesarean rate, but also actually less need for an in-animal intensive care. So I do think that, barring other reasons and there are some that we could go into this is where we’re at right now in the literature, and the bottom line is that we should probably be teaching this as a preferred method of induction, in the starting point at least. The article prior to that one in the same edition reviews all of the different methods of induction, including things you might not have heard of, things that have been tried or are currently available, or in research. So it’s a great review article for residents or medical students who are interested in learning about all the things you can do to induce labor.
Antonia: 12:13
Yeah, so check it out. Yeah, so it might not be the most comfortable method or maybe the most convenient, especially if you’re doing like outpatient police sometimes or midnight nurse, starting the induction there.
Howard: 12:26
Yeah, there are pragmatic reasons why you might want to do it to affect time of delivery or, as you said, a lot of these are moving to outpatient now and misoprostol is not appropriate for outpatient, so but if you have somebody in the hospital and your job is to get them delivered as soon as possible, this is probably the way to do it.
Antonia: 12:42
All right. Well, there was another nice expert review in that same edition about trial of labor after cesarean and the different factors that affect the risk of uterine rupture, and I don’t think there’s anything really groundbreaking or surprising here, but it is a nice summary of what literature exists right now, and it applied the ABCD levels of evidence from the USPSTF to help supply some evidence-based recommendations about risk factors that could affect patients’ decisions for whether or not to pursue a trial of labor, about maybe their prior deliveries or prior surgeries, risk factors regarding the current pregnancy, risk factors from intrapartum if they are already laboring, and then it also discusses some issues about the intrapartum management of those TOLACs.
Howard: 13:37
Yeah, they do a nice job of, as you said, giving the levels of evidence for these recommendations along with the level of certainty that we have for the conclusion and appropriate references, of course. So, for example, a patient with a previous uterine rupture or a classical fundal T or J extension or a myomectomy entering the uterine cavity or more than two prior cesareans, well, those are all D recommendations, which means that we recommend against it. And of course, we all know that Two prior cesareans was a C recommendation, meaning that you have to weigh the individual patient risks and preferences and come up with a joint decision. May be appropriate for some patients and not for others. And then every other case that they listed was either an A or a B recommendation, including low vertical hysterotomy or an unknown hysterotomy and all types of uterine closures in the previous cesareans, meaning single layer, double layer, single lock, double locked, et cetera. All the variations, all of these were equal recommendations. One wasn’t better than the other and one wasn’t stronger than the other.
Antonia: 14:37
Yeah, so that might actually be surprising for some people. And another thing was that all of the patient-specific risk factors outside of the uterine scar types that we just discussed, all of them were either A or B recommendations. So that included things like the inter-delivery interval even short-interval pregnancy, still A or B and whether there was an infection present during the prior cesarean, since you might be concerned that infection made for a weaker scar no, not according to this. And then actually having twins or polyhydramnios in the current pregnancy with a prior cesarean. Those were both A recommendations and I think that’s interesting because we generally counsel our patients after cesarean that you should try to wait at least a year before conceiving so that your uterine scar can heal, and there’s at least a theoretic concern that having a short interval pregnancy after cesarean could increase the risk of rupture in the next pregnancy. Of course, there’s not good data on that and that’s one thing that they’ve reviewed here.
Howard: 15:46
I think it can be true that your risk is slightly higher if you have a short interval pregnancy of uterine rupture but overall that’s not a reason not to do it Right. So the counseling is appropriate. If you’re planning a VBAC, please have 18 months between your deliveries, but we’re not going to stop you or we shouldn’t stop you from having a trial of labor just because it ends up being 12 months.
Antonia: 16:08
Yeah, it’s not like it brings it to the level of a prior classical C-section and then having twins or polyhydramnios or maybe fetal macrosomia. Those are all considered postpartum hemorrhage risk factors because they distend the uterine cavity more than normal in a pregnancy. So it’s nice to know that that distension still doesn’t increase the uterine rupture risk, at least not to a degree high enough to discourage VBAC. But I’m sure there’s doctors out there who probably still don’t support VBACs for any of their patients that have twins or polyhydramnios patients. And I’ve also heard I’ve heard of some physicians basically saying if the patient is past 41 weeks she can’t try to VBAC.
Howard: 16:56
Yeah, or even 40 weeks, I’ve heard. So I think the importance of all these things is just that these are reasons that doctors use to avoid offering patient of trial of labor. And in the same vein, again, all types of uterine closures were B recommendations. So many physicians will tell patients that because they had a single layer closure, for example, that they shouldn’t be allowed to have vaginal birth after cesarean, and there’s no evidence that that’s any more true than if they had a double layer closure. You shouldn’t be allowed. It’s the same risk. And again, all these other things.
Howard: 17:25
I think that when women go in for counseling, then it’s well, you had an infection and or you had a short interval pregnancy and they oh, I looked, they only did a single layer closure. You’re just looking for some reason. It’s kind of like an external cephalic version where, sure, you’re nulliparous, but that’s not a reason not to try. It’s just a factor that may be associated with less success, but you still try. So I think that’s the importance of these. Now, some of the intrapartum risk factors that they looked at included augmentation of labor with oxytocin and various induction methods, and the only DE recommendations here, of course, were prostaglandins in the presence of a viable fetus, which we know, that of course.
Howard: 18:06
They did list oxytocin going higher than 20 on the dosage. That comes from a single study from 1980, so there’s just a dearth of knowledge here. But if you want to be conservative with that, only increase your oxytocin to 20. Now the only A recommendation that they offered in this section was spontaneous labor. So again, it’s nice if you have spontaneous labor in terms of your success. But other things like double or single balloon catheters or labor augmentation with oxytocin, performing an external cephalic version, having epidurals or higher epidural dosages, amnioinfusion if needed, amniotomy and all the other sort of common things we do in labor. They were all B recommendations and remember that a B recommendation still means that we recommend the service. It’s just with less certainty than an A recommendation, and here too there are people who have very specific things about epidurals and don’t want patients to get epidurals if they’re having VBACs and that’s simply not recommended.
Antonia: 19:03
Yeah, I think the opposite.
Howard: 19:05
Yeah.
Antonia: 19:06
Yeah, we could talk about that. They also don’t recommend outpatient cervical ripening, so this wouldn’t be an outpatient Foley candidate. But all the other things that we might do commonly during labor are recommended for TOLACs in this review article. Anyway, this whole edition is several hundred pages long.
Antonia: 19:29
Other review article that’s definitely worth reading out of those several hundred pages is a similar evidence-based review for management of the third stage of labor to prevent adverse maternal and neonatal outcomes, and they have several summary recommendations, including that oxytocin is the most effective uterotonic for postpartum hemorrhage, both vaginal and cesarean deliveries, and that delayed cord clamping is a level A recommendation.
Antonia: 19:57
And of course they also recommend early skin-to-skin contact and controlled cord traction during the second stage, and I’ll just reiterate here we said this in a prior episode the traction does not forcibly pull the placenta away. I still get requests to not pull on the cord after delivery from patients, but the placenta will still take as long to separate as it otherwise would have if we weren’t doing anything. It’s just that it helps pull it out of the canal after it’s separated so it doesn’t just sit there blocking clots and maybe masking a hemorrhage or causing the uterus to over distend and bleed even more. So anyway, just everyone remember that, especially if you have a patient requesting. See if you can help clarify some misconceptions there. The authors of this review article also do not recommend tranexamic acid or nipple stim for prevention of postpartum hemorrhage, and they don’t recommend uterine massage while the placenta is still in the uterus. So I thought that was interesting too.
Howard: 20:59
Well, and again this is sometimes there’s a dearth of evidence about things, but if you think about it, if you are pulling traction on the cord while the placenta is still there and you put your hand on top of the uterine fundus to do massage, you could pull and massage your way into a uterine inversion.
Antonia: 21:14
Yeah.
Howard: 21:15
So we give the oxytocin to do the uterine contractility portion. We don’t need to rub the uterus to make it contract. So, yes, and also, women don’t need to push when the placenta is being delivered either right, for probably the same reason. But those are just cultural things, I think, in our specialty. But yeah, there’s several other great articles in that edition and great reviews that are good for a basis of knowledge, particularly for residents and students. Both that Volume 1 and Volume 2 of this series is definitely worth looking through.
Howard: 21:42
There’s an important new trial we’ll switch journals published in the April edition of Obstetrics and Gynecology about late preterm antenatal steroids and reduction of neonatal respiratory complications. In fact, that’s the title. That’s how clever I am. So, based upon essentially one study that was called the Antenatal Preterm Steroid Trial, or the ALPS trial, it’s become practice now to at least opportunistically administer betamethasone to pregnancies at risk of delivering between 34 to delivering before 34 weeks gestation. But the ALPS trial had some cautionary data when it was published about the risk of neonatal hypoglycemia and more recent data have shown that that’s probably not that concerning. We’ll talk about that too, but the original trial showed a very minimal benefit from steroids in that window.
Antonia: 22:38
Yeah, I believe you talked about that new data when I was not on the podcast that one time but I did listen to episode five, season five, episode nine.
Antonia: 22:50
So the original ALPS trial showed no difference in NICU admission rates or in the need for mechanical ventilation or really anything else significant for the babies, but it did show a small decrease in the need for supplemental oxygen in a subset of patients that were born by a cesarean. So it really has found broad wings, with a very minimal subset of patients having had any benefit, and that’s a pretty minor benefit, I’d say. I think it’s one of those things where people just concluded that, yeah, it might have a marginal benefit and no obvious harm, so we should just do it for everyone. But again, in that sense we’ve perhaps created a false standard of care.
Howard: 23:35
Yeah, and just to beat a dead horse, it’s the same issue where we don’t have, here, in this case, replicated trial showing effectiveness and we don’t have a large magnitude of effect, so it really shouldn’t be practice changing that one study shows a very minimal effect that hasn’t been replicated, and this is the mistake we made with McKenna.
Howard: 23:54
This is a mistake we make with a lot of things, and then it has a life of its own, and it’s hard to stop doing something that feels like it’s standard of practice. Now it gets recommended and it’s in our guidelines. So this new study, though, was done over a two-year time period, but it was performed in southern India, and that’s interesting, I think, because you might conclude that a resource-poor environment could show potentially greater benefit from using beta methadone in these early newborns, because, well, their NICU technology and neonatal care just isn’t as widely available or perhaps as good as it might be in a resource-rich country like the United States. So you could argue that you would find a more obvious and enhanced benefit from an intervention like this in India than you might in the United States.
Antonia: 24:41
All right, well, is that what they found?
Howard: 24:44
No, they found no difference between the group that got steroids and the group that got placebo at all.
Antonia: 24:50
And this isn’t the only study to have found no benefit right.
Howard: 24:54
That’s right. So there were a couple of studies even before ALPS. So Porto and colleagues published a study in 2011, which was a randomized controlled trial of the same thing again that was published in the British Medical Journal. They had 320 women whom they randomized and they found no difference in need for ventilatory support or any other outcome in the steroid group versus the placebo group. And then, just before ALPS, there was another trial published in 2015 in the Lancet, and this was an international trial in six countries, and this is actually a cluster randomized trial over a three-year time period that was sponsored by the Eunice Kennedy Shriver NICHD here in the US, and they found that not only did it not decrease neonatal mortality, but in those low-resource countries they were concerned about an increase in neonatal deaths and maternal infections associated with the group that got steroids.
Antonia: 25:45
And those were both published before the ALPS trial.
Howard: 25:48
Right and that ALPS trial was then published in 2016. And this is one of those large MFM network trials that was published in the New England Journal of Medicine. Practically all of them are all have the same author groups, all from the MFM network, and those trials tend to get a lot more attention and credibility than other papers, especially international studies like the one in the Lancet and the British Medical Journal. But again, this trial’s actual implications were very minimal in terms of decreased transient need for oxygen in the subset of patients born by cesarean and, at the time at least, we were concerned about a nine percentage point increase in hypoglycemia among the infants who had been exposed to steroids.
Antonia: 26:30
But ACOG still changed their recommendations to give steroids in the 34 to 37 week period after the ALPS trial, I believe despite those previous two trials showing no benefit and despite the very weak benefit that was indicated in the ALPS trial, without really much regard to that increased risk of hypoglycemia.
Howard: 26:52
Yeah, and I think this was even controversial at the time and again like not to go too far with this, but one of the issues is that the author group who is in the MFM network are also largely the editors of our American journals and the folks who make the guidelines at ACOG. So it’s a small group of folks and they believe that their one study is better than international trials or any other evidence, and so I think this is a problem that we’ve seen. This is the same story with the BEAM trial Exact same, well similar author group, same publication strategy. Disagreed with prior studies but became at least a soft recommendation, despite it disagreeing with other evidence. Now about this trial, the ALPS trial.
Howard: 27:34
In 2017, right after it was published, there was a Journal Club article that reviewed the ALPS study published in Nature. So it reviewed the available evidence, including the ALP study, and concluded that the decision to use steroids in the 34 to 37 week time frame was certainly not a confident one, and they expressed concern about the very weak data and the lack of long-term follow-up, especially at the time. Again, we were concerned about hypoglycemia issue. So they found in that assessment that the number needed to cause one case of hypoglycemia was only 11, while the number needed to prevent one administration of surfactant was 77. And they concluded as well that the only benefit was less need for high-flow oxygen for about two hours and nothing else.
Antonia: 28:19
So, yeah, a lot of these studies take a very weak possible benefit and then recommend the treatment anyway just because, well, it might work a little bit, especially if there’s no really potential harm or major harm noted. But what makes this unique is that one in 11 kids in the treatment group had hypoglycemia, which really could be associated with some long-term neurologic outcomes that hadn’t really been followed out at all.
Howard: 28:49
Right, and that’s what we thought then, and it’s a concern, and so I think the importance of that now is just to illustrate how we got here, that this became a recommendation despite that concern not being answered and despite the weak benefit and despite prior negative trials. But again, I think this is what we tend to do in OBGYN we’re honestly, we’re not practicing evidence-based medicine here. So along comes this new study, in which this is the lead study in this edition of the Green Journal, and it concludes that there’s no benefit from using it in late preterm period. Now they also found no harms from administering the betamethasone, and the hypoglycemia numbers in this new study were similar in both groups, so the hypoglycemia thing probably has panned out to be much of nothing. There was an increased risk of chorioamnionitis in the betamethasone group, but though the numbers were different, this didn’t reach statistical significance.
Antonia: 29:45
All right. So we’ve been giving late preterm steroids for a while, and now this is another kind of hit against it. So what next?
Howard: 29:53
Well, there’s also an editorial in the same edition of the Green Journal that accompanies the article, and they point out that the study was stopped at its midpoint because of futility. This new study and that’s interesting in itself when the review board didn’t allow it to continue because the intervention was clearly futile. They also point out that this study is very similar in design to the ALPS study, with the main difference being that it was an international study in a low-resource country and the ALPS study is a trial in a low-resource country and the ALPS study is a trial in a high-resource country. So, interestingly, the editorial writers recognized that the other trials that we mentioned exist and their findings and their conclusion is that studies from high-resource countries may not be applicable to studies from low-resource countries. Well, that’s true, rather than concluding that the ALPS trial just contained a false discovery, which is also probably true.
Antonia: 30:41
They just couldn’t allow for the ALPS to possibly be the one that was mistaken, so they seemed to hedge a little bit in this editorial, concluded that we should keep giving the steroids in the 34 to 37 week gestational age group despite these really disappointing results. So it’s interesting to read between the lines here, like why would you not conclude that the three large international trials are telling the real story and the one us trial is the one with the false positive finding? Maybe there is multiple comparators problem or some other issue? I think it shows some inertia in our thinking, at least in the US, and honestly a preference for American-based research, even though that international trial you mentioned was funded by the American National Institute for Child Health and Development.
Howard: 31:34
Yeah, it’s a bit tenuous that they concluded that children in India in the editorial might not have benefited as much from steroids, because this is their conclusion that people in India perhaps are less nourished than people in the US and that sort of commentary isn’t helpful. It’s just wild speculation without any evidence. And again, a much more logical thought might be that the ALPS study contains a false positive finding. It’s almost like we don’t believe that literature published from the United States or from the MFM network is capable of having false positive findings, especially when in the subset analyses and non-replicated data. And that’s the point of replication and designing a study appropriately. Even when you find a finding there’s a good chance it’s a false positive finding. When you replicate it then you diminish that chance, help validate it. So here we’ve got three studies that say it doesn’t work and one study that found the most minor possible benefit and we go with that.
Antonia: 32:28
Well, hopefully at least. If nothing else, this might lead to another trial and give more context to the understanding that steroids between 34 to 37 weeks probably is not that valuable and we really shouldn’t change our overall management of patients in that window just to give them the steroids and that already was the conclusion. For example, you shouldn’t delay somebody’s delivery in the late preterm period if they need to be delivered, just so that they can get the full dose of steroids. If anything, always it was just an opportunistic administration.
Howard: 33:05
Well, I will say, the issue of hypoglycemia from ALPS that we were concerned about back then apparently has turned out to not be that meaningful in both term and late preterm children. So though, that being said, even the ALPS trial excluded diabetic mothers, presumably because they would have a more dramatic increase in blood sugar in response to the steroids that could be more harmful to their newborns. But in addition to the study we already mentioned that didn’t find a difference in hypoglycemia, there was a publication earlier this year in the Gray Journal that was a secondary analysis of the ALPS data, and these children have been followed along, and they’re now more than six years old, and they found no difference in a variety of neurologic outcomes. So both the ALPS study and these other studies have not found hypoglycemia to be an issue.
Howard: 33:48
Of course, I could also point out that the children have no difference in neurologic outcomes, or other issues too. So maybe the steroids didn’t have any long-term benefit either would be a conclusion from the same study. But I do worry about this trap of assuming that just because something may not be clearly harmful, then we should use it or give it or do it just on the off chance that it might help a particular person in a group. I think we have to have clear evidence of benefit before we do anything to a patient and I worry that our profession slipped into this trap that I might start calling the DES trap, because that’s what folks did. They knew it didn’t help, but they didn’t see any evidence of harm until the next generation.
Antonia: 34:27
Yeah, it’s kind of a theme on this podcast, I think. So, just like we’ve said so many times before, we have to balance our desire to do something, anything just give them something, treat them against our ethical limitations of not harming patients if what we’re doing is not of clear benefit to them.
Howard: 34:48
The therapeutic imperative is very powerful.
Antonia: 34:50
All right. Well, let’s move on. I know you didn’t want to miss this recent publication about whale menopause that was published earlier this year in the Nature Journal.
Howard: 34:59
Wow, are we going to do two articles in one episode from nature?
Antonia: 35:03
Well, yeah, if it’s about whales, then yeah. So it’s a fun thing to talk about the evolutionary advantage of things we see like menopause or PCOS. We talked about that before us, we talked about that before, but with menopause, if you didn’t know this, only six mammal species alive today have menopause in their females, and there’s about 6,000 different species of mammals, so one one thousandth of them get menopause.
Howard: 35:32
There you go Shows how unique human women are. Well, humans and five others. The five others are all different types of toothed whales, so human women, and then you have killer whales, false killer whales, beluga whales, narwhals and short-finned pilot whales. So that’s a traditional list of species of mammals that have menopause, but there are some researchers will point out, that have questioned this idea that there’s only those six, and some believe that if an animal lives long enough, then more mammals would eventually go through menopause and maybe they just die too soon to get there. But in the natural order of things, those are the only ones that we routinely observe as having a long enough lifespan and then have some long period of time of life where they live with a loss of their reproductive function. But there are some rare examples of very long-living chimps, for example, and a few other animals that have exhibited menopause in later life, and we’ll put an article that talks about that too.
Antonia: 36:30
Yeah.
Antonia: 36:30
So it’s routine for those six species of mammals, which is the humans and then the five different types of whales, to have menopause, Whereas in any other animal if they have menopause it’s really rare.
Antonia: 36:44
It’s like an anomaly which in those cases it could still be a natural decline in ovarian function due to aging, or maybe even a disease state, like maybe some kind of autoimmune destruction of the ovary or something else, some kind of autoimmune destruction of the ovary or something else. Either way, researchers and evolutionary biologists have all sorts of theories about what advantage or purpose menopause may serve, especially in the species that it’s normal for them to have it. This new article in Nature illustrates that all of the female mammals who have menopause tend to live about four decades longer than mammals who do not have menopause, and that bolsters the idea that I bet this was so interesting that menopause creates a social structure where the elder females provide support for the extended family and grandchildren. That overall contributes to longevity of all of them, for themselves, but also for their whole society. So in other words, at least if that’s true, then you could say menopause is a valuable trait that helps advance the survival of the species and the society.
Howard: 38:01
Yeah, because the species does better, as the animals interact with each other better and live longer and have more education and et cetera. Right, so I think that’s the traditional idea, those groups of toothed whales that they talk about. They have very complex social structures and they have intergenerational interactions that people study. The older females don’t compete with the younger females for mates, but they still get to raise their young, and the social structure becomes more dynamic and complex and interdependent, so this is called the live long hypothesis.
Howard: 38:34
Still, though, it’s interesting, because 150 years ago, the average human woman died before she would obtain menopause, at least in terms of averages.
Howard: 38:41
The average woman died at around age 40. And, of course, a girl born today can expect to live probably more than double that Now. That being said, the child mortality and infant mortality rate were so high back then, as well as the maternal mortality rate, but it wasn’t like the average woman just got to 40 and keeled over, but it was more that many women died in infancy or in childbirth or otherwise in younger ages. But if you survived all those things, older women would live to older ages that are not too much different than women see today. So 40 was an average, but the extremes was a bipolar distribution, I guess. So it’s probably not that we’ve discovered menopause in human women more recently because they live longer now. It’s been around for as long as any human woman has ever lived, past 50 or so. But that’s the interesting contrast with these whales there’s evidence that they’ve acquired menopause over time, and over that time the researchers have seen that they live longer, and even the males live longer, as menopause has become a feature of their species.
Antonia: 39:45
Yeah, and the other interesting feature that humans and then only certain other mammals have is concealed ovulation, or hidden estrus is another way to say that which is essentially the lack of any visible or detectable signs, even like pheromones that would indicate that the female is nearing ovulation or that she’s in heat or anything like that.
Antonia: 40:06
So cats release pheromones that would indicate that the female is nearing ovulation or that she’s in heat or anything like that. So cats release pheromones that are obvious to their potential mates. Baboons have swelling and redness of the vulva that is visually very obvious to their mates, but human women have no external signals and really for the most part no internal signals. If a woman wants to know if she’s ovulating, she has to really get very detailed with tracking and maybe checking her temp and cervical mucus and getting some LH tests and all of that, and even even that’s not perfect. So in other words, if you didn’t realize what we know today about ovulation and kind of natural family planning cycles and LH tests, then most people would not know when their fertile window was. And of course we know that now, but probably even a hundred years ago nobody knew that.
Howard: 41:00
Yeah Well, this is another fun dinner party conversation that you can have. You can debate why this concealed estrus could be a potential advantage to the species. So I think the leading idea is a so-called paternal investment hypothesis, and that essentially means that males have to mate with the females multiple times and invest more and more time in their relationship, if you will effort into maintaining that relationship with a female, if he wants to pass his genes on, and so perhaps this promotes a monogamous structure and male support, as well as creating a relationship that emphasizes the reproductive fitness of both partners, because if you know your partner a little more, you’ll know more about their reproductive fitness.
Antonia: 41:43
I bet IVF is a very extreme example of this paternal investment hypothesis too. But yeah, so there are other ideas. So there’s another theory called reduced this is terrible but I’ll just mention it the reduced infanticide hypothesis, which basically states that because of that prolonged relationship where it took so many times of mating to finally conceive and have a baby, because of that hypothesis, then the male is less likely to kill the newborn, which sadly does happen a lot in other primates, for example. And I don’t know, is there any kind of thought process behind that? Do primates actually look at a newborn and think, oh, that’s that other baboon’s baby and not mine, so let me just kill it? It’s not like that really would have a clear advantage for the species anyway, but it happens. And I don’t know. You don’t like this one, I don’t like this one, but it’s out there, yeah.
Howard: 42:44
Well, Well, I. One of the things that makes humans is, in theory, we do care more about the larger social group and survival, the species, in deference to individual survival. But a lot of animals, they, they don’t care about anything but passing their own genes along and they’re rather selfish and their systems exist in that way. So, yeah, I think that that is. The idea is that you’re competing with other lions, for example, things like that is that maybe you’re competing with other males and so one way of competing with them is to kill their offspring. So, but this is more common than menopause, this concealed estrus among different species. But humans apparently are at least the only primates who live together normally who have concealed estrus among different species. But humans apparently are at least the only primates who live together normally who have concealed estrus. But throughout the mammal world there are other species who share this characteristic. It’s seen, for example, in dolphins and some species of deer and some shrews and just a lot of other mammals. It’s not the common norm, but it’s out there.
Antonia: 43:44
I think, another interesting trait. I’ll just so. I think human babies are more helpless for longer portions of their lives than really any other mammal that I can think of, and the survival advantage there potentially could be that it really forces the parents and maybe even the whole community to spend a lot more time with the babies, protecting the babies, raising them, and that might balance their survival even against overpopulation in a way.
Howard: 44:13
And throw menopause in. And the grandmothers are there too. Yeah.
Howard: 44:18
So all kinds of fun conversation starters for you guys now you guys now, well, another concept we talk a lot about, without maybe explicitly saying it this way, is the idea that we take descriptive statistics and we make them into sort of normative statistics. We look at a population and measure it and then, whatever the averages are and stuff, we say that that’s normal and then we tell people they’re insufficient if they don’t meet those averages. So if we look, for example we talked about calcium and vitamin D If we look at how much calcium or vitamin D the average person eats per day, and then we define those who don’t consume the average as insufficient, without necessarily showing that less intake is associated with the disease state. We do that with a lot of things. So in pregnancy we do this with descriptions of nutrient intakes and all sorts of things.
Howard: 45:10
But we also do it with how much weight does she gain? How many calories does she need per day of certain iron or other nutrients? How much should she have a day? So these questions aren’t answered necessarily with a randomized trial to see if one amount of something is better than another amount. But again, we just look at a description of what’s happening in a population on average and then call that normal and then tell anybody who’s not doing that within some parameter that they’re abnormal. So, all that to say, there’s a new study this month in the Lancet that looks at how much weight gain recommendations, that looks at how weight gain recommendations might actually be harming obese patients.
Antonia: 45:47
Yeah. So this was a population-based cohort study in Sweden of almost 16,000 pregnancies complicated by obesity. Most of them had class one obesity, which is BMI 30 to just under 35. And essentially what they found was that women who gained weight below the lower limit of the current IOM recommendations did not have any increased risk of any adverse outcomes. And in fact for the women with class three obesity so the PMI over 40, weight gain that was less than the current recommendations actually had less adverse events. So they did better when they gained less than what is recommended. So the authors of this called for the Institute of Medicine recommendations for weight gain for obese pregnant women to just be completely removed.
Howard: 46:40
Yeah, I think people would be surprised to know how little of our advice on things like this about nutrition or weight or activity is not based on any evidence at all.
Howard: 46:51
Obviously, we’ve talked a lot about activity restrictions during pregnancy and more recently after surgery, and that these things are just culturally inherited.
Howard: 46:59
But in this case we’ve looked at what obese women tend to do with weight gain during their pregnancy and then we’ve told women that they should do whatever that 95% confidence interval is for that population, without realizing that that whole population may be doing something harmful and be too far to the right of that bell-shaped distribution. If you think about it that way, in the past doctors really emphasized the amount of weight gain and measured it every day, every appointment, and looked at it, and patients come to believe, if they’re not gaining enough weight, that somehow they’re harming their fetus or causing growth restriction. I tend to tell my patients who are worried about their weight that I don’t check their weight to make sure that they’re gaining enough weight, but to make sure, rather, that they’re not gaining too much weight, because all of the negative consequences associated with weight gain during pregnancy are associated with too much weight gain. Very little evidence that too little weight gain, even in normal weight patients, has any real meaning for the pregnancy.
Antonia: 47:56
Yeah, and these are separate concepts. It seems like people will think of these running together, but pre-pregnancy weight is a separate concept from how much they gain during pregnancy. So someone who’s underweight at the start of their pregnancy still has risks. It’s not like it’s better to be underweight than to be overweight or obese at the start of a pregnancy. And obviously we’re not wanting patients to think about all of these photos of women in media that promote eating disorders and stuff. We don’t want people to get in their heads about that and think, well, I obsess about, are they gaining too much weight either? That’s not healthy. All of this is just to say if you’re able to eat and hydrate you’re not throwing everything up but you’re able to keep some things down then and you’re still not gaining at a certain rate, then don’t worry, you’re getting something. You’re getting enough.
Howard: 48:51
Yeah, and most women by 20 weeks, just in the normal course of things, have lost a little bit of weight and that’s okay, they do fine, the babies do fine, and I think we’ve become very comfortable with the idea for obese women actually dieting and they may need to diet to maintain weight and it might even be okay if they lose weight in certain weight classes, but that’s not the way people thought 20 or 30 years ago yeah, and I wouldn’t really call it dieting necessarily, but just like eating healthy.
Antonia: 49:19
And if that’s a change from if they used to just eat nothing but extra large pizzas and donuts, then just eat a normal healthy person. At 20 weeks your baby will probably still be 12 ounces. 50th percentile, be fine, all right. Well, let’s hit a listener question. I don’t think we’ll have time for more than one of these today, but here’s the one. So the listener says how do I know how much bleeding is too much? In the operating room I see some attendings Bovie every last red blood cell and others seem to be relatively carefree and close patients. That I know would make some of my other attendings freak out. Signed clot concerned in California. Well, that’s cute. I love that.
Howard: 50:01
Yeah Well, I think this is a really difficult question, but an important one. So let’s just talk about cesareans. We can talk about hysterectomy, we can talk about anything that has blood loss, but cesareans as an example. So the length of surgery for cesarean deliveries is all over the place.
Howard: 50:18
I’ll put a link to an analysis of over 30,000 cesareans that were done, all with a standard protocol, at a single university-affiliated medical center over a little bit more than a decade and they found that about 5% of those cesareans took longer than 90 minutes, with an average operating time of about 53 minutes and an interquartile range of between 44 to 64 minutes.
Howard: 50:44
But of course, some of the cesareans at the other end of that took less than 15 minutes. So they saw a fairly wide range in average operating times, despite using a standardized technique and being at a single institution. So I think a lot about what makes some surgeons consistently slower than other surgeons and how we can teach them to be a little bit faster. And I think one factor of all that is being able to balance. What is a safe and acceptable amount of bleeding, or how much do you sit there and track down every little bleeder, just like Clock Concerned is asking. You’ve got to maintain good visualization while you’re doing a surgery and how much do you allow to bleed while you continue to go through? And then how much time do you spend at the end of the surgery chasing down every little red blood cell?
Antonia: 51:30
Yeah, you and I have talked a lot about surgical efficiency over the years and the level of tolerance for bleeding or potential bleeding is a big part of that, I think. Also just confidence with steps and operating room efficiency and things like that do matter. But at cesarean delivery in particular, a lot of time can be spent chasing every last potential red blood cell, as they said, either with the Bovie or with sutures. But isn’t it right that you don’t use the Bovie at all during cesarean?
Howard: 52:01
Yeah, that’s right and I just looked it up and I’ve done a little bit over 1,200 cesareans in my career and the vast majority of those have honestly been done by learners, by residents etc. Not by my own hands. But I made it a point a long time ago earlier in my career to never allow a Bovie, even on the surgical field. So there’s not a chance of using of using, and so virtually every single one of those cesareans has been performed without a Bovie.
Howard: 52:27
It’s very easy to sit there if you have that and want to buzz every little spot of bleeding, and some of those might warrant a suture, some of them don’t, and I guess what I’m saying is if they don’t need a suture, they don’t need a Bovie either, and if it does need a suture, the Bovie would likely be insufficient anyway.
Howard: 52:43
So people waste a lot of time with the Bovie and they could have either left it alone or found a deeper bleeding vessel or retracted artery or something and sutured it. So I mostly do this, not because I’m super anti-Bovie, but because I wanted to show residents and students that all that cautery that they might be used to at a cesarean is just unnecessary, and then they have something to compare to when they see other surgeons who might spend 10, 20, 30 minutes sitting there cauterizing with a Bovie, dissecting with it like a scalpel, chasing down every last little bleed, etc. And I’ve, by the way, not taken any of those 1200 plus patients back to the operating room because of a delayed bleed, or none of them have had a rectus sheath hematoma or any of those things that you might be saying to yourself would happen if you didn’t Bovie all the time.
Antonia: 53:32
Yeah, especially in cesareans, because of the time-sensitive nature of let’s get the baby out first and worry about everything else later. For those we may encounter some superficial bleeding on the way to the uterus, but in those cases we’ll just keep going so we can get the baby out and then make a mental note, come back to that bleeder if it’s still bleeding and often we’ll find that it’s not bleeding anymore it simply self-resolves that maybe the vessel spasms itself off and then the blood clots and you don’t even need to touch it. And that might not be the same mindset for any other kind of less urgent surgery, let’s say maybe an abdominal hysterectomy or something where we’re traditionally taught that each layer has to be hemostatic before we can possibly move on to the next step.
Howard: 54:21
Yeah, I think of the closure of a vaginal hysterectomy where you have still the long-weighted speculum in you’re irrigating, you’re looking for bleeding and there’s just a little something that still you’re looking at and you’re not comfortable with it yet, and so you just keep looking and keep looking and keep looking and what you might need to do is put the short-weighted in and reef the peritoneum on the cuff and that bleeding goes away. So actually progressing and going on through the surgery not only gets you done faster, it actually solves the problem. Sometimes you have to come back because it’s still bleeding despite that. But yeah, we get in these patterns where we just sit and stare and Bovie and irrigate and stare and Bovie and irrigate.
Antonia: 55:01
Yeah. So I would tell our listener from California just observe the attendings who are quicker in their surgery and then see if that overlaps with the attendings who are less worried about complete hemostasis than others, and then figure out if any from that group especially if there’s some overlap there, if they have good outcomes. And if any of them do, then model those patients or those doctors. So it’s hard to teach a person objectively how much is the right amount to worry about hemostasis. Some attendings will make residents overly concerned about every single drop of blood and, like you said, sit there, stare at it 30 seconds or more, hold pressure, stare again, call for a hemostatic agent, stare again, cauterize, stare again, and by that time you’ve spent a good 20 plus minutes on just that step that another attending would have just moved right past. And then in almost all cases the outcomes are the same.
Howard: 56:04
Well, certainly not saying that people should ignore frank bleeding that’s rapidly accumulating or covering up the operative field. Arterial bleeding needs to be dealt with usually, but I think the question is about this gray area in between more of a drip or a subtle ooze or something like that. This could also apply to bleeding after a vaginal delivery. How much bleeding is too much after a vaginal delivery, for example? Or a DNC or a tenaculum site, or after a uterine evacuation just about everything right? People have a different tolerance for what they think is acceptable. So the outcomes are probably worse when you have a prolonged surgery compared to if you just ignored a little bit of venous oozing and enclosed the patient. So we do know that length of surgery is directly related to things like surgical site infection risk and thrombotic risk. So if you leave a patient open at the time necessary and for an additional 10 or 15 or 20 or 30 minutes because you’re chasing down every last red blood cell in the world, you’re probably doing more harm than good. Now I put a link to a very small randomized trial. There’s not a good literature basis for this. It is a frustrating thing to study and teach, I think. But in this trial women were randomized who were women undergoing cesareans, to either use of the BOVI and cautery versus no use of the BOVI, and this is primarily they were looking at the abdominal wound and they found that surgical site infections were 23% in the Bovie group compared to 15% in the non-Bovie group. And I’ll also put a link to a letter to the editor from a few years ago in the Gray Journal called the 15-Minute Cesarean, where a physician from Oregon I think can’t remember he was struck at a publication he was reading about how long the average operating times were for cesareans in that study and he offered a few of his own tips and I don’t agree with all of them. But in essence, using a standardized evidence-based approach that we’ve discussed on here, he uses a modification of the Joel Cohen or Misgav-Ladach technique is quicker.
Howard: 58:03
And one of the big points that this author makes is to not use the bovine during surgery and I couldn’t agree with that part anymore. In fact I’ll quote a part of his last three paragraphs. He says the second biggest time saver is to avoid electrocautery until the very last as a cutting tool. The scalpel is much faster and less destructive way of getting to and partially through the fascia, typically, all those bleeders encountered on entry will stop by closure and cautery will not be needed at all. It’s also faster and gentler on epithelial surfaces to use suction or saline rinse rather than to continuously sponge to keep the field clean.
Howard: 58:36
A nice side effect of the aforementioned approach is that pelvic adhesions seem to be very rare or even on higher order repeats. I have no formal study on the subject, but I’ve personally performed more than 4,000 cesareans and nearly always find a completely clean pelvis on re-entry. Of course, that’s his own experience and there is missing evidence here, but I think a lot of people would agree with that. And just basic principles of surgery and the effect that the cautery has on tissues and things like that. Well, it’s going to promote adhesions and it’s going to promote poor healing as a necrosis tissue. So it’s this hard thing where we don’t want to take the blood supply away from the wound.
Antonia: 59:13
Yeah, someone that’s done over 4,000 cesareans and does them in 15 minutes, that would be one to watch for sure. So teaching this is a modeling approach and people will become accustomed to what they see repeatedly. I think you have to keep in mind, of course, to distinguish venous from arterial bleeds. An arterial bleed does need to be taken care of in some way, and a lot of times small ones, you can just put on a hemostat for a minute and then just remove it and they’ll be fine. You might not even have to suture it. Larger ones maybe put in a finger of eight, but you still don’t necessarily need the Bovie for those. If you already have it out, that’s fine. But venous oozing from peritoneal edges does not need to be attended to unless you know that they have a platelet disorder or some other kind of bleeding dyscrasia. But this does have to be taught by example. So again, I’d encourage our friend, the California clotting concern person, to look to your attendings, who have good outcomes and who are less concerned about bleeding than the other more nervous attendings.
Howard: 1:00:22
Yeah, you just have to pattern yourself and your practice after people that you trust and who you see have good outcomes and seem comfortable in the operating room, things like that. The key to being a resident, I think, when you’re learning, is distinguish between the good attendings and the average ones and then try to model the good ones. And the truth is everybody does something good, does something well, and you probably pick good things from different people and be a mixture of all of them.
Antonia: 1:00:47
Well, I think we should wrap up again for today. So the Thinking About OBGYN website. We’ll have links to what we discussed about. Also, check out our Instagram and we’ll be back in a couple weeks.
Announcer: 1:01:02
Thanks for listening. Find us online at thinkingaboutobgyn.com. Be sure to subscribe. Look for new episodes every two weeks.
