Ada Popek

Dr. James McGregor of the US again took center stage, with his proposal 			to aggressively treat infection-mediated premature delivery. Citing published studies to demonstrate that 1/3 to 			1/2 of all prematurity is infection-related, Dr. McGregor then counted down the six infectious entities which he 			felt, in spite of limited clinical experience for the most part, were prime targets for this practical and money saving 			crusade.
 			
 			Dr. McGregor suggested that significant inroads could be made against premature delivery and its monetary and human 			costs by screening "early and often" during pregnancy, starting at the first prenatal visit, for:

Group B streptococcus associated with asymptomatic                   bacteriuria;

According to Dr. McGregor, the screening and treatment of these entities during pregnancy would cost about as much 			as the cost of 12 minutes for a premature neonate in the neonatal intensive care unit. Dr. McGregor then went on 			to challenge the audience to screen and treat for these infections as a preparation for pregnancy, initiating such 			screening perhaps 6 months prior to a planned pregnancy, for the optimal benefit. Again, Dr. McGregor explained 			that, although the science behind this protocol seems solid, aiming at reducing the inflammatory mediators which 			place patients at risk for premature labor and delivery, there is not, as yet, appropriate evidence to support 			all of these recommendations.
 			
 			Dr. McGregor summed up his presentation by citing published data which indicated that treatment of a gravida in 			labor, and the prevention of her delivery (in the face of an otherwise healthy and stable fetus), increased the 			infant's survival by 2% for every day gained in utero, and increased the infant's normalcy beyond survival by 1% 			per day gained in utero. Thus, if a baby were held in utero for 10 days, there would be a gain of 20% in mortality 			and 10% in survival intactness. A worthwhile goal.

: This is an Opinion by the author In the UK they are currently involved in a huge multicentre study into the relationship between infection and PPROM / prem labour (ORACLE Study). The case is not clearly proven and more importantly the ability to stop the bad outcomes by intervening with antibiotics is not clearly established.

Reporting for OBGYN.net at ESIDOG, Dr. Joseph Pastorek is a private consultant in Louisiana, in the Greater New Orleans area, and a long-time researcher and speaker on obstetric and gynecologic infectious disease topics. He is also the Louisiana State representative for OBGYN.net. Any immediate comments or feedback on the conference may be directed to Dr. Pastorek at 

Articles

From the 7th European conference of Infectious Diseases in Obstetrics and Gynecology - October 5, 1999, in Istanbul, TurkeyReporting for OBGYN.net at ESIDOG, Dr. Joseph Pastorek

Proposal To Aggressively Treat Infection-mediated Premature Delivery

:  	"This is Richard Polin, I’m the Director of Neonatology at Columbia  	Presbyterian Medical Center and Professor of Pediatrics at the College of  	Physicians. I’m here right now in Salzburg, Austria at the end of a one-week  	course, which is a course on maternal and infant health. We’ve invited Dr.  	James McGregor to speak about obstetrical issues, Dr. Robert Clancy who is  	from the Children’s Hospital Philadelphia to speak about pediatric  	neurology, Steven Don from the University of Michigan speaking about  	pediatric cardiology, William Goldman from Wyeth Laboratories speaking about  	infant nutrition, and Richard Markowitz from the University of Pennsylvania  	speaking about pediatric radiology.

At this course there are sixty invited fellows from just about every  		country east of Vienna that used to belong to the Soviet Union. So we  		have people from the Ukraine, Russia, Mongolia, Croatia, and Albania -  		every former Soviet Republic. They get to spend a week here in Salzburg  		at the site where they hold the Salzburg Seminars, all their expenses  		are paid including meals and airfare. At the end of the course, they’re  		given a set of slides they can take back to their own country and the  		hope is that the information they learn here will be delivered to their  		friends and peers through lectures and informal conversation."

: "This is Jamie  		McGregor, and I’d like to ask Dr. Richard Polin about new advances in  		terms of infection and inflammation during pregnancy and the problem of  		cerebral palsy which has so far resisted all of our attempts at doing  		better."

: "Yes, I certainly  		agree with your last statement that the incidence of cerebral palsy has  		not changed substantially despite many improvements in the quality of  		both obstetrical and neonatal intensive care. The greatest areas that I  		believe for improvement in the outcome of high-risk neonates will come  		from interventions aimed at in utero or intrauterine inflammation. And  		there’s mounting evidence, some of it fairly direct, much of it  		epidemiological studies demonstrating a relationship between  		chorioamnionitis and a later development of cerebral palsy both in  		premature and term-newborn infants. The other focus that I think we are  		learning to do better at is avoiding many of the complications of  		newborn intensive care such as intraventricular hemorrhage and paying  		closer attention to blood pressure and stabilization of vital signs. The  		final area which I think may have an impact on the outcome of cerebral  		palsy is the use of head cooling or hyperthermia in babies that have,  		unfortunately, been asphyxiated."

: "The notion is that  		there’s a critical period of time after an infant has been asphyxiated,  		no one’s quite sure of the exact time period, it’s probably up to about  		six hours. There is both animal data and now human data on about thirty  		newborn infants that cooling of the head and body - and we do this by  		using a plastic cap that fits over the skull through which cold water  		circulates - the baby’s body core temperature is reduced to 34 ½ degrees  		centigrade. The temperature of the brain is even cooler than that,  		probably a couple of degrees cooler. And the animal data says that if  		you cool the head of an animal that’s been asphyxiated, you can prevent  		the apoptotic injury, which occurs probably over a period of months  		after prenatal asphyxia. Even if head cooling is not a major  		intervention, the hope is that head cooling will prolong the critical  		time period for other kinds of interventions such as insulin-like growth  		factor which is now being talked about as a intervention for perinatal  		asphyxia."

: "What about other  		suggestions of using agents which can scavenge oxygen radicals which are  		released during hypoxemia?"

: "If the mechanisms  		of brain injury are multiple and hypoxic, ischemic encephalopathy and  		include almost assuredly free radical injury, glutamate induced  		neurotoxicity, direct cytokine induced neurotoxicity, and finally  		apoptotic injury that occurs over a long period of time, and I think for  		us to be successful, we’re going to have to look at all the mechanisms  		involved in brain injury. Magnesium was a therapy that we hoped would  		have looked at the issue of glutamate neurotoxicity but in the studies  		done today, it doesn’t look like there’s a big enough signal that  		magnesium will be neuro protective."

: "Would you  		speculate on which of these ways of possibly preventing cerebral palsy  		would actually be the most practicable in the near future? Would it be  		screen, treat, and prevent infections during pregnancy or would it be  		more rapid recognition of encephalopathy after birth?"

: "I would say the  		largest signal is going to be the screen, treat, and prevent infection  		in pregnancy. As few as 20% of cerebral palsy or as much as 35% may be  		due to infections which begin in utero. So in terms of the possibilities  		of preventing cerebral palsy, I think therapies aimed at identifying  		women with a potential for infection, and identifying that infection at  		the earliest time point is probably the therapy which is likely to  		achieve the greatest success."

: "I would like to  		thank Dr. Richard Polin who is Chief of Neonatology at Columbia  		University School of Medicine. Thank you Rich."

OBGYN.net Conference CoverageFrom American/Austrian Conference, Salzburg Austria March 4-10, 2000

Prevention of Neonatal Infection

 "I am Dr. Umid       Sharapov, and I’m a resident in Pediatrics at Tash Kant Medical       Institute in Uzbekistan. Three years ago I had the privilege to be       selected and to participate in the Salzburg Seminars which were held in       Budapest. Actually, this is my third participation in the seminar, the       second time I have visited Salzburg and this is my third time at an       American Austrian Foundation seminar. Up until its collapse, medical       community in the former Soviet Union felt separated and had a lack of       information. We are grateful for this opportunity to come and participate       at this seminar and be exposed to the latest information by such wonderful       and outstanding lecturers from the United States. This enables us to       improve our practices and to share the information with our colleagues       back home."

:       Thank you very much, Umid. It’s always a pleasure for us to see you and       to all learn together so much, certainly we learn from you more than I can       say. Thank you very much."

Importance of Salzburg Seminars

: "I’m Dr. Robert       Clancy, I’m a Child Neurologist from the Children’s Hospital in       Philadelphia, Pennsylvania and I deal with newborns with acute brain       disease. My interest is in pharmacological protection, and I think what I’m       interested in looking into the future are the role of the caspases as a       class of drugs that inhibit apoptosis. Unfortunately, the only caspases I       know of right now are those that are given inside the ventricle so that’s       not a very convenient route."

:       "So could you tell us what caspases are because some people think       those are the enzymes that have to carry forward to the apoptosis."

:       "The caspase inhibitors are what we’re looking for. I guess the       notion is that we’re not even sure what exactly is the cause of brain       damage in newborns - to what extent is it frank

necrosis, to what       extent is it apoptosis, or some combination of that. So that’s one of       our research areas with congenital heart disease is now to look at the       pathology and try to determine when we see lesions on the MRI - are they       actually necrotic or are they apoptotic because that may take us in one       direction or the other. What’s on our immediate horizon are the use of       drugs like Desflurane which are very broad spectrum with respect to neuro       protection so they turn out to inhibit the apoptosis, necrosis, and       glutamate. It really is a shotgun approach."

:       "Isn’t desflurane an anesthetic agent?"

:       "It is, it’s an anesthetic agent that pharmacologically can mimic       KTP-ases

which are part of the biology of what you were looking       for."

:       "Now cell activation and also like preconditioning, so in       preconditioning we might induce a sub lethal injury to the heart or the       brain so that when it’s repeated a day or so later, even a larger insult       does not produce damage. The question is can we mimic preconditioning       because preconditioning does protect an organ from ischemia, and the       answer is, in fact, that Desflurane will mimic some of those changes from       preconditioning. So if it’s an operating room situation, you can add       Desflurane over or on top of the ordinary anesthesia like for congenital       heart disease surgery and continue that drug until they’re in the       post-op period. Then do it as an experimental trial, a blind and       randomized trial and hopefully show that you can protect the heart and the       head. Because one of the things that’s sort of obvious but no one talks       about is that even after birth asphyxia if you don’t protect the heart,       you have a harder time protecting the head because if the heart is       asphyxiated too, and then even after the baby is born, they’re not       profusing their brain so that the two have to be protected together. The       heart and brain should be protected together and things like Desflurane       can do that."

:       "So to sum up, you’re looking at neuro-protective interventions       which you could actually give ahead of or at the time of that intervention       which might even include a birth where there is asphyxia associated."

:       "Exactly, we don’t know what the window of opportunity is to treat       after an event. Honestly, if you could do it before the event that would       be fine, and that day may come but there must be some period, some grace       period after the fact of asphyxia that you can still make things better.       You may not have a chance to protect 100% but if you could protect it       somewhat that would be worth the effort."

:       "And these can even be translated into adult medicine because, say,       patients who are going on the pump for heart surgery or patients who       suffer an acute stroke, they may benefit from your kind of research as       well."

:       "Exactly, and again, the advantage of this is simply that you know       ahead of time when you’re going to have surgery. If you can’t show it       in a controlled situation like this, it’s going to be very hard to do it       in an open field situation where the person can be found down and       different diseases, different times, different temperatures, and things       like that."

:       "So from your view as a Child Neurologist who works in the nursery at       the Children’s Hospital in Philadelphia, Pennsylvania - the most       important intervention we could do in terms of cerebral palsy or birth       asphyxia would actually be to prevent the situation such as infection and       inflammation which actually may be occurring during pregnancy."

:       "Right, and obviously for anything neurological once it’s a done       deal you’re in deep already

at that point. I would like to think       that there will be controlled trials of recognizing a chorioamnionitis       early, treating, immune modulators, or something to interfere with that       process before it’s simply recognized at birth that the baby’s       depressed."

:       "In essence, perhaps in a football metaphor, how would you sum up       everything?"

:       "Thank you. That was Dr. Robert Clancy, he’s Professor of       Pediatrics & Neurology at the Children’s Hospital of Philadelphia.       Thank you."

Prevention of Cerebral Palsy

click           here for RealAudio/Video version

 "My     name is Jamie McGregor, and I work at the University of Colorado. This is my     friend and colleague, Dr. Ken Spielvogel, he's one of the residents in     Obstetrics and Gynecology at the University of Colorado. He's going to start     a new column that's called, "The Naked Ob-Gyn." Ken, can you tell     us about that column?"
     
     

 "The     column would be very nice for residents in the sense that it would give them     inside information into life before residency in terms of interviewing and     tips along the interview trail; life during residency, being able to have     conversations over the Internet with other residents in terms of their     training experiences, as well as preparing for life after residency in job     interviewing and job placement across the country."
     
     

 "You're     not going to talk about good restaurants in Philadelphia or New York or …?"
     
     

 "That     goes hand in hand with inside information. People going to conferences could     electronically ask people in Philadelphia about the best place to go dancing     or the best band to hear while in Philadelphia."
     
     

 "What     if they've got a problem with their program?"
     
     

     "Absolutely, that would be excellent to be able to have resources of     particularly people who are in administrative - sectional representatives -     to be able to have a question-answer period with them in terms of policy,     procedure, and modifications."
     
     

 "And     then sort of talk together."
     
     

 "We're     really looking forward to your column, "The Naked Ob-Gyn."
     
     

 "Thank you, Jamie. Nice     talking to you."

From ACOG - Philadelphia, Pennsylvania - May, 1999

The Naked Ob-Gyn

click 						here for RealAudio/Video version

http://www.obgyn.net/avtranscripts/SalEST_mcgregor.htm

 "Hello, my name is Ada Popek, and I'm with a company by the name of Biex. We're a relatively new young company out of California that has developed a new technology for assessing patients at risk for preterm labor. With me I have Dr. McGregor, who is with the University of Colorado. Doctor, can you tell us a little bit about the test and how you're using it in your hospital system?"
             
             

 "Sure Ada. The test is called 'SalEst,' short for salivary estriol. It's collected in saliva, which is a painless way to collect hormonal measurement, and it measures estriol. Estriol is a hormone that's produced by the baby and the placenta. Estriol measurement is actually a way to tell what time it is on the placental clock, and women themselves can actually plot how their pregnancies are doing in terms of getting the signal to go into labor, and this is done painlessly. We ask women to actually measure their salivary estriol themselves once a week, and we plot the results. It's really fascinating, and patients really appreciate knowing when their clock is about to go off."
             
             

 "What gestational age do you begin using SalEst?"
             
             

 "We actually begin at 24-weeks gestation and measure every other week, but I think actually the most information we can get starts at 28- to 34-weeks. Many of our patients and their families want to know when the clock goes off, so they're actually anxious to get the test every week, even after 34 weeks."
             
             

 "Doctor, which patients do you think the test is most valuable for?"
             
             

 "I think it's valuable for everyone because we're really looking at the natural signal that the placenta and the baby give to make the mother's uterus go into labor and, actually, this is valuable information for everyone. I think the focus in medicine will be to apply it to patients who are at high risk, who've had a prior preterm birth before, or who have twins or other kinds of problems. But in fact, this is a everday test looking for the natural signal of labor and birth."
             
             

 "Do you find that the patients are really compliant and accept this test easily?"
             
             

 "Yes, Ada. The test is simple. There's no vena-puncture, there's no pain, and actually, its just sort of collecting saliva. Pregnant women often times have a lot of saliva-in medicine we call that 'ptyalism,' and it makes it very easy to collect this test. It's not gooey, it's not messy, and it doesn't even have to be refrigerated. You just simply seal it in a little plastic container and mail it off."
             
             

 "How long is it before the results are forwarded to the physician?"
             
             

 "The results come overnight by U.P.S. Actually, the results are done by 10:30 the next morning, and they get faxed or e-mailed to us."
             
             

 "At that point the doctor would use the results, I assume, to determine a pathway or treatment for the patient?"
             
             

 "Yes, if there's a concern about preterm labor and if the salivary estriol was well below the threshold of the alarm level, then, in fact, that's very reassuring. Many patients are, appropriately, very concerned about having a preterm birth because they know what the consequence of that is. So if it's low, that's very reassuring. On the other hand, if it's higher, above the threshold, that's of concern too. What we do at the University of Colorado is ask those patients to come in to be seen, and we go over them from head to toe. We see if we can find a reason for this premature signal, and the vast majority of folks who actually do."
             
             

 "Doctor, how accurate or telling is this test? Will we catch every preterm labor?"
             
             

 "No. It may be that preterm labor results from other kinds of problems that don't have to do with natural, physiologic mechanisms-trauma, a bleeding episode, or a medical induction for labor-that really won't be determined because those have other causes. But for the normal, everyday pre-term birth, this test is very reliable-over 80%."
             
             

 "Now let me ask you one more question - do you tend to get many false-positive results with this test?"
             
             

 "No, the positives are really positive. That's fascinating; it's nature's own signal. So in fact, when it's positive, that's of concern-it's not like a test that's kind of wishy-washy. This is a test that's actually surging, the hormone is actually surging, so you don't get false-positives. You could get false-negatives, but they're caused by other processes like infection, bleeding, trauma, preeclampsia, or things that we physicians induce patients for."
             
             

 "Now do you think by watching the trend or the results of the SalEst test, that that's the most important way to utilize the test or to look for a cut-off value?"
             
             

 "Ada, the patients themselves, as well as the care providers-doctors and nurses-are actually happier to plot each weekly level so they can see how a pregnancy's going. It's fascinating. We live out in Colorado, and relatives from the east coast who want to come to be there for the birth can actually ask, 'how's the plot going?' Or, they even want to be faxed the results."
             
             

 "Thank you very much, Dr. McGregor."
             
             