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RE HOT subject: 3-D vs ALARA vs Safety in embryosFrom: James S. Smeltzer (gaperina@mindspring.com)Tue Oct 22 21:35:06 2002
For more information see review: Maternal hyperthermia is a proven teratogen in all species studied. The HS response is inducible in early embryonic life but it fails to protect embryos against damage at certain stages of development. An embryo must absorb a threshold 'dose' of heat if defects are to be caused, the dose being the product of the level and the duration of elevation above the normal maternal temperature. The lowest elevation causing damage is 2-2.5 degrees C. Low elevations require longer durations and as the elevation increases, the time required is reduced logarithmically. Heat-induced defects are most common in the central nervous system (CNS) and include open neural tube, microencephaly, microphthalmia and neurogenic contractures. Apoptotic cells are found in these organs soon after threshold doses of heat. The periods of high susceptibility are brief, occurring at the time of organ induction and, paradoxically, at this stage, chaperone protein synthesis is at high levels, presumably to protect this process... in Apoptosis, the heat shock response, hyperthermia, birth defects, disease and cancer. Where are the common links? Edwards MJ.Cell Stress Chaperones. 1998 Dec;3(4):213-20. School of Anatomy, The University of New South Wales, NSW, 2052, Australia. and: Teratogen update: gestational effects of maternal hyperthermia due to febrile illnesses and resultant patterns of defects in humans. Graham JM Jr, Edwards MJ, Edwards MJ. Teratology. 1998 Nov;58(5):209-21. Medical Genetics Birth Defects Center, UCLA School of Medicine, Cedars-Sinai Medical Center, USA. jgraham@mailgate.csmc.edu This review has covered the pertinent literature concerning the teratogenic effects of hyperthermia in man and experimental animals. This is the first teratogen that was initially discovered in animals and then subsequently found to be a cause for concern in humans when similar patterns of defects were observed. Hyperthermia is a physical agent with a dose-response curve for abortions and malformations, but these effects can be mitigated in some circumstances by the heat shock response (HSR). We have reviewed the known functions of HSR and provided some insight into why embryos have some protection following an initial dose of heat, if it is sufficient to initiate the response. Thus, by reviewing the effects of hyperthermia in experimental animals, as well as malformative and protective mechanisms of teratogenesis, we have attempted to understand the effects of human hyperthermia teratogenesis. Hyperthermia in the chick embryo: HSP and possible mechanisms of developmental defects. Buckiova D, Kubinova L, Soukup A, Jelinek R, Brown NA. Dint J De Bio. 1998 July;42(5):737-40. Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Prague. buck@biomed.cas.cz Although hyperthermia is an established teratogen in all species studied and the cellular heat shock response is well known, the mechanisms of developmental deviation remain obscure. We have used a chick model system in which fertilized eggs containing embryos at presomite and/or early somite stages (HH 4-10) were exposed to 45 degrees C for 180 min. Six hours following treatment we did not observe any overt morphological disturbance, but at twelve hours following exposure (when controls reached HH 11-13) embryos exposed at late streak stages (HH 4-6) exhibited severe malformation of the head. Embryos exposed later (HH 6-9) manifested spina bifida at the thoracic and lumbosacral levels. Mirror image heart looping was also observed in 20% of these embryos. Paraxial mesoderm was apparently unaffected. Changes in cell proliferation and induced cell death preceded morphological changes. We used acridine orange and confocal laser microscopy to demonstrate that hyperthermia induced cell death in neural folds starting 6 h following treatment. To assess cell proliferation, we used BrdU incorporation for 4 h. Immunodetection on paraffin sections demonstrated that proliferation was inhibited 6 h after treatment. Heat-exposed embryos exhibited the heat shock response, with protein expression reaching a maximum 4-6 h following heat treatment. Malformed embryos showed an intense heat shock response for a further 6 h. The levels of induced heat shock proteins were similar in the affected neural tube and in the heart, where neither induced cell death nor malformations were observed. Hyperthermia, teratogenesis and the heat shock response in mammalian embryos in culture. Edwards MJ, Walsh DA, Li Z. Dint J De Bio. 1997 Apr;41(2):345-58. Department of Veterinary Clinical Sciences, The University of Sydney, N.S.W., Australia. Hyperthermia is a recognized teratogen in animals and there is strong evidence that it also causes significant damage to human embryos. Studies with induced hyperthermia in pregnant animals defined the defects which are produced, the susceptible stages of development, and threshold doses of heat required to cause defects. The in vivo experiments lacked precision because of variability of embryonic development at a given conceptual age, varying maternal responses to agents causing temperature elevations, the difficulty in measuring embryonic temperature and the possibility that defects were caused by toxic changes in maternal metabolism. These variables were eliminated by the use of postimplantation whole rat and mouse embryo cultures, which were exposed to various doses of heat at closely defined stages of development. The studies showed that heat acts directly on embryos and that elevations of 2 degrees C and greater sustained over early rat organogenesis cause defects mainly by causing apoptotic cell death especially in the developing central nervous system. A moderate, non damaging exposure is followed within 15 min by protection for up to 8 h against a more severe and otherwise teratogenic exposure. The protective heat shock response is accompanied by a reduction of normal protein synthesis and concurrent synthesis of heat shock proteins (HSP90, 71, 47, 27). Most HSP in these families are also present constitutively in embryos, probably having important roles in protecting newly synthesized proteins from aggregation and facilitating folding into their normal functional configurations. The appearance of induced HSP and hsp mRNA at known sites of thermal damage suggests a protective role. Heat induced cell death by apoptosis is a feature of teratogenic damage to the developing brain. Apoptosis could be a by-product of a damaging heat exposure because of a priority favoring induction of the heat shock response over the normal gene program for organogenesis, survival being achieved at the expense of normal development. and Exercise at high temperature causes maternal hyperthermia and fetal anomalies in rats. Sasaki J, Yamaguchi A, Nabeshima Y, Shigemitsu S, Mesaki N, Kubo T. Teratology. 1995 Apr;51(4):233-6. Department of Obstetrics and Gynecology, University of Tsukuba, Ibaraki, Japan. Hyperthermia is thought to be a teratogen in many animal species and also in humans. It has been reported that hyperthermia caused by sauna, hot tub, or fever during the early stages of pregnancy is related to an increased risk for neural tube defects. During exercise, especially in hot conditions, body temperature can also rise to fairly high levels. Thus, we can surmise that hyperthermia induced by exercise can also cause fetal malformation. To investigate this hypothesis, pregnant rats at 9 days of gestation were divided into four groups. In the first group, the animals were made to swim for 30 minutes in water at a temperature of 40.5 degrees C. In the second group, they were restrained and immersed in water for the same time at the same temperature. In the third group, the rats were forced to swim in water at 36.0 degrees C. The fourth group were controls. The core temperature of the rats was measured during these procedures. On the 18th gestational day, fetuses were extracted by cesarean section. The elevation of maternal core temperature was significantly greater in the first group than in the other groups. In the first group, 69% of fetuses had various external anomalies. No anomalies were found in the other groups. Our results show that exercise in hot conditions caused the elevation of core temperature and resulted in fetal anomalies in rats. Intracranial temperature elevation from diagnostic ultrasound. Barnett SB. Ultrasound Med Biol. 2001 Jul;27(7):883-8. CSIRO Telecommunications and Industrial Physics, Sydney, Australia. stan.barnett@tip.csiro.au Tissues of the central nervous system are sensitive to damage by physical agents, such as heat and ultrasound. Exposure to pulsed spectral Doppler ultrasound can significantly heat biologic tissue because of the relatively high intensities used and the need to hold the beam stationary during examinations. This has significant implications for sensitive neural tissue such as that exposed during spectral Doppler flow studies of fetal cerebral vessels. Recent changes in the FDA regulation allow delivery of almost eight times higher intensity into the fetal brain by ultrasound devices that incorporate an approved real-time output display in their design. In this situation, ultrasound users are expected to assess the risk/benefit ratio based on their interpretation of equipment output displays (including the thermal index, TI) and an understanding of the significance of biologic effects. To assist in the assessment of potential thermally mediated bioeffects, a number of conclusions can be drawn from the published scientific literature: the amount of ultrasound-induced intracranial heating increases with gestational age and the development of fetal bone; pulsed spectral Doppler ultrasound can produce biologically significant heating in the fetal brain; the rate of heating near bone is rapid, with approximately 75% of the maximum heating occurring within 30 s; blood flow has minimal cooling effect on ultrasound-induced heating of the brain when insonated with narrow focused clinical beams; the threshold for irreversible damage in the developing embryo and fetal brain is exceeded when a temperature increase of 4 degrees C is maintained for 5 min; an ultrasound exposure that produces a temperature increase of up to 1.5 degrees C in 120 s does not elicit measurable electrophysiologic responses in fetal brain; for some exposure conditions, the thermal index (TI), as used in the FDA-approved output display standard, underestimates the extent of ultrasound-induced intracranial temperature increase. Effects of pulsed ultrasound on embryonic development: an in vitro study. Ramnarine KV, Nassiri DK, McCarthy A, Brown NA. Ultrasound Med Biol. 1998 May;24(4):575-85. Department of Medical Physics and Bioengineering, St. George's Healthcare NHS Trust, London, UK. kramnarine@ed.ac.uk Whole-embryo culture was used as the model system to study the effects of pulsed ultrasound on embryonic development. Rat embryos (9.5 days old) were exposed to a wide range of ultrasound levels at ultrasound frequencies between 1-4 MHz for 30 min in vitro. After 48 h in culture, absolute control, sham and treatment embryos were assessed for viability, morphology, growth and development. At an ambient temperature of 37 degrees C, no significant effects were observed for spatial peak temporal average intensities below 4 W/cm2 or peak negative pressures below 1.9 MPa. At higher acoustic levels, there was a significant increase in the number of nonviable embryos and the number of morphological abnormalities in viable embryos increased. Abnormal cephalocaudal flexion and abnormal head development were the most common gross morphological abnormalities. Both thermal and nonthermal bioeffect mechanisms are involved. Barnett SB, Walsh DA, Angles JA. Ultrasonics. 1990 May;28(3):166-70. Ultrasonics Institute, Chatswood, NSW, Australia. An in vitro whole-embryo culture system was used which allowed ultrasound to interact directly with rat embryos, at 9.5 days of gestation, under conditions of controlled temperature. Neural plate damage, expressed during a critical period of forebrain development, was evaluated 48 h post-insonation. Ultrasound-induced effects were thus identified in the absence of significant temperature changes or complications from the influence of maternal physiology. Exposures to 3.2 microseconds pulses of 3.14 MHz ultrasound at a PRF of 2 kHz and 1.2 W cm-2 intensity (ISPTA) for durations of 5, 15 or 30 min produced no major morphological abnormalities at a temperature of 38.5 degrees C. Embryonic response to stress was evidenced by changes in protein synthesis, and delayed development was indicated by a reduction in somite number. These effects were enhanced when the insonation temperature was elevated by 1.5 degrees C. We must be cognizant of minimum exposure time and power insonating embryos needed to do our job and avoid unnecessary exposure. The dancing fetus 4-D stuff clearly does not respect that boundary IMHO. It also makes it difficult to measure a CRL. Jim
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> [From: James S. Smeltzer; -- --------------------------------------- > [To: Multiple recipients of list ULTRASOUND; > [Date: Tuesday, October 22, 2002 10:00:09 PM >Philippe, > >My personal opinion is that the issue is heat. The MI does not >aggregate total heat transfer to the patient or any object presumed to >be an embryo. Here opinion ends. > >The heat flux to and out of an embryo depends on the conditions, the >energy delivered, the energy absorbed and the tissue perfusion. It >depends on time only to the extent that an equilibrium flux rate is not >achieved at a temperature safe for the embryo. If you insonate a larger >field, which happens to be an entire embryo, at MI power levels proven >safe for a sub sample of the field (2-D sonography), you do not >necessarily provide safe (Nonteratogenic) power (equilibrium >temperature) to the embryo. > >I stand absolutely on the fact that there is a pioneer (or from the >embryo's point of view - guinea pig) risk as long as actual monitored >and measured experience with an actual drug or modality in human embryos >does not preclude any measurable increase in problems - theoretical >considerations and animal experiments aside. > >I stand absolutely on the fact that thalidomide was proven safe in two >species before given to women who were pregnant (not legally in the US, >thanks to the FDA which prefers to let Asian and European fetuses be >used as post-marketing guinea pigs). > >I stand absolutely on the fact that heat is a proven teratogenesis in >humans. > >I will state categorically that women who subject their embryos to >"cute" 3-D shows are subjecting them to unknown risks. > >I will state categorically that early 3-D embryonic sonography >necessarily exposes the early embryo to more sound energy than is >necessary to document a heart beat and crown-rump length, and are, >therefore, inherently violating the ALARA principle. > >Besides these facts, the rest is conjecture. > >Jim > >--------------------------------------- >> [From: Philippe Jeanty. MD, PhD; >--------------------------------------- >> [Address: jeanty@TheFetus.net; >--------------------------------------- >> [To: Multiple recipients of list ULTRASOUND; >> [Date: Tuesday, October 22, 2002 01:55:14 PM >>Hey Jim.... >>Are these comment documented evidences or personal opinions ? >>Do folks who use 3D expose the fetus longer then folks who do not ? >what is >>the average time of exposure in your environment ? What typical values >of MI >>and TI do you have on your images ? >> >>I would think that the issue is way more complex then your note let it >>appear, and that your note, by simplifying too much may give a >distorted >>view to reality. >> >>Would you possibly reconsider the statements you made ? >> >> -----Original Message----- >>From: ultrasound@obgyn.net [mailto:ultrasound@obgyn.net] On Behalf Of >>James S Smeltzer MD >>Sent: Monday, October 21, 2002 10:19 PM >>To: Multiple recipients of list ULTRASOUND >>Subject: Re: no subject received Wed, 16 Oct 2002 14:56:28 -0500 >> >>At 02:59 PM 10/16/2002 -0500, you wrote: >>>Hi my name in Fabiola savinovich and I am 29 weeks pregnant. i would >like >>>to know were in MIami can I get a 3D ultrasound performed. Thanks >>> >> >>Hi Fabiola! >> >>Usually a 3-D ultrasound does not obtain more information about your >baby >>than a skilled examiner gets with a regular ultrasound. It does >deliver >>more total energy to the baby. We know this is heat. We also know >that >>heat is a known cause of birth defects in the first 3 months inside. >Right >>now lots of women are using their babies as guinea pigs to see if this >is >>enough heat to be a problem or not. Once a few million women have had >this >>test and had follow-up on their babies we may know that it is safe. >Then >>again we may know that it is risky. >> >>If you or the baby's father have some problems with the development of >the >>skeleton or certain physical deformities that might be inherited, then >this >>may be a better test for you despite this potential risk. Otherwise I >>would talk the unknown risk and benefits over with your doctor. In >general >>it is usually wise to let someone else use their baby as a guinea pig >and >>avoid exposing your baby to unknown and new things until they are known >to >>be safe, unless they are the best possible medical alternative for some >>other reason. >> >>Jim Smeltzer, MD
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