Women often do not realize they are pregnant at five weeks, when they may be subject to fevers, infections or take prescription or recreational drugs that can disrupt the regulatory system. Could this explain some de novo copy-number variations?
Significant heating of cells in 5 week old embryos is known to result in increased risk of teratogenic defects and death. (1,2,3) It is known that the fetus is already slightly hotter than the mother, and has no way to easily get rid of excess heat. Conditions present in early pregnancy, such as lack of blood perfusion, may favor bioeffects. The embryo has no blood circulation until about 10 weeks, therefore, the fetus before 10 weeks has not way to easily rid itself of heat by carrying it away. Thermally induced teratogenesis has been shown in many animal studies, as well as several controlled human studies; However, very subtle effects cannot be ruled out and indicate a need for further research, although research in humans may be extremely difficult to realize.
At about weeks 4 to 5, the gestational sac is about the size of the
eye (2.5 cm in diameter), and by week 8, it is around 8 cm in diameter. There is no perfusion in very early gestation. Only at about weeks 10 to 11 does the embryonic circulation actually link up with the maternal circulation. At that stage, there is a switch from previously hypoxic conditions to normo-oxic conditions and a cascading of radical scavengers (eg, superoxide dismutase)
to help deal with the free radicals.
Thermal index (4) is when ultrasound raises temperature of the target by 1°C or more. Any biological effect of ultrasound that is accompanied by temperature increments less than 1°C above normal physiologic levels is called a mechanical
effect. Mechanical effect includes processes that arise secondary to chemical reactions initiated by free oxygen (cavitation) and sonoluminescence ( the emission of short bursts of light from imploding bubbles in a liquid excited by sound.. Pulsed ultrasound can produce damage to biological tissues in lab animals using ultrasound levels considerably greater than the output of diagnostic devices used on fetuses. However, low-intensity pulsed ultrasound is used clinically to accelerate the bone fracture repair process and induce healing in
humans. Low-intensity pulsed ultrasound also has been shown
to enhance repair of soft tissue damage and accelerate nerve
regeneration in animal models. Although such exposures to low
intensity do not appear to cause damage to exposed tissues,
they do raise questions about the threshold that might
induce potentially adverse developmental effects in the fetus.
1.Marinac-Dabic D, Krulewitch CJ, Moore RM Jr. Center for Devices and Radiological Health, Food and Drug Administration. The safety of prenatal ultrasound exposure in human studies. Epidemiology. 2002 May;13(3 Suppl):S19-22.
2.Bly S, Van den Hof MC; Diagnostic Imaging Committee, Society of Obstetricians and Gynaecologists of Canada. Obstetric ultrasound biological effects and safety. J Obstet Gynaecol Can. 2005 Jun;27(6):572-80.
3. Ultrasonography, diagnostic in Ob/Gyn (PositionPaper). www.aafp.org/online/en/home/policy/policies/u/ultrasonography.html [Accessed 2 Jan 2010].
4.Marshall NE, Fu R, Guise JM. Impact of multiple cesarean deliveries on maternal morbidity: a systematic review. Am J Obstet Gynecol. 2011;205(3):262.e1-8.
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Thank you for your detailed response regarding fetal and maternal thermoregulation, which was quite detailed and well supported. I am not concerned as much with teratogenesis as in what you suggest as possible subtle effects. Although I did not mention prenatal ultrasound in my question, that -- along with fevers or drug reactions -- could certainly be a source of elevated maternal temperature in the areas subject to scans.
I wonder if a geneticist could chime in about the possibility of heat causing de novo copy-number variations (CNVs)? Certain de novo CNVs have been associated with autism (with some crossover to ADHD). However, the CNVs cannot be assumed to be causative -- many people with the same CNVs do not exhibit symptoms of autism. My conjecture is that CNVs might be red flags that there has been an elevation in maternal temperature or some other intrusion that may or may not affect fetal outcome.
Carl Sagan, in describing the workings of DNA in the book "Shadows of Forgotten Ancestors," said of DNA replication errors: "Some are induced by a cosmic ray or another kind of radiation, or by chemicals in the environment. A rise in temperature might slightly increase the rate at which molecules fall to pieces, and this could lead to mistakes..."
Teratogenesis is a catch all phrase which includes subtle genetic and gross genetic effects.
I wonder what you are really looking for.
It is my understanding that teratogenesis specifically denotes a malformation of some kind and does not include "subtle" effects that cannot be determined at birth, such as neurological disorders.
What I am really look for is what I asked: Can elevated maternal heat cause copy number variations and if so, would an embryo that is only five or six weeks old be vulnerable to copy number variations if there were an elevation in maternal heat. The source of de novo copy number variations, which are not inherited, does not seem to be well understood, yet we live in a world of cause and effect so I am trying to determine what might be causing de novo copy number variations associated with neurological disorders such as autism and ADHD.
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