Re: RE HOT subject: 3-D vs ALARA vs Safety in embryos
From: Terry J DuBose (tjdubose@juno.com)
Tue Oct 22 22:01:11 2002
Go get'um, Jim... ;-) Terry
On Tue, 22 Oct 2002 21:37:52 -0500 "James S. Smeltzer"
<gaperina@mindspring.com> writes:
> 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
>
> ---------------------------------------
> > [From: James S. Smeltzer;
> ---------------------------------------
> > [Address: gaperina@mindspring.com;
> ---------------------------------------
> > [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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