1. Hyperthermia in pregnancy
2013.4.9.
주산기 전임의 이민영

2. INTRODUCTION
Heat?
• Heat has always been part of the natural environment
– Major force in the evolution of existing animals and plants
– During their evolution, animals have acquired the capacity to maintain
their body temperatures within a relatively narrow range
• The margin between the existing mammalian body temperatures
and lethal levels is relatively small
– Evolution of even higher body temperatures might not be possible unless
novel genetic mutations overcome this barrier

3. INTRODUCTION
Normal body temperatures
• Average body temperature of most mammalian species
– 37–40°C
• Each animal species has its own normal temperature range and
cell proliferation proceeds optimally at this level
(Mazza et al., 2004)
 37℃ for humans (oral temperature)
 38.3℃ for mice (Shiota, 1988)
 38℃ for horses, 38.5℃ for cattle (Blood and Radostits, 1989)
 38.5℃ for rats (Webster et al., 1985)
 39℃ for sheep and pigs, 39.5℃ goats (Blood and Radostits, 1989)
 39.5℃ for guinea pigs (Edwards, 1969)

4. INTRODUCTION
Dinurial variation
• Temperatures are lower during sleep and rest and higher
during wakefulness and physical activity
– Normal body temperature averages about 37℃(98.6℉)
– Normal temperature consists of a range, usually±0.6–0.88C

5. What is hyperthermia?

6. INTRODUCTION
Hyperthermia
• Definition
– Abnormal elevation of body temperature
• Causes
– Most often occurs from a fever due to illness
– Febrile infections
– Environmental exposure to heat sources
• Hot tubs, baths and Sauna
– Heavy exercise
• Especially in conditions of high heat and humidity
– Some drugs
• Amphetamine, Cocaine, Phencyclidine (PCP)
• Methylenedioxymethylmethamphetamine (MDMA; “ecstacy”)
• Lysergic acid diethylamide (LSD)
• Salilcylates, Lithium, Anticholinergics, Sympathomimetics

7. Fever VS hyperthermia??

8. INTRODUCTION
INTRODUCTION
What are differences?
Fever Hyperthermia
Change in hypothalamic set Failure in thermoregulation
point
Involves cytokines Can exceed >41℃
Diurnal variation Can be detrimental
Rarely exceeds 41℃ Absence of diurnal variation
Complications are rare

9. Hyperthermia & Pregnancy

10. ANIMAL STUDIES
INTRODUCTION
Why hyperthermia is concern?
• Hyperthermia was the first teratogen in animals that was
subsequently proven to be teratogenic in humans.
• Animal studies have demonstrated heat to be a significant
cause for reproductive problems in a wide variety of
mammals
– Range from embryonic death and abortion to teratogenically induced
anomalies
(ex. : NTD, Growth retardation, Development defect)
– Heavily dependent on the dose and timing of the exposure
(Edwards, ’86; Edwards et al., ’95)

11. ANIMAL STUDIES
INTRODUCTION
Teratogenecity
• A critical teratogenic threshold (In mammals)
– Elevation is 2.0 to 2.5°C above the normal core body temperature
(Edwards et al., 1995)
– Even very prolonged exposures to elevations of less than 2°C do not
appear to cause defects, so it appears justified to cite 2°C as a
threshold elevation without specifying a duration
In humans, threshold temperature for teratogenicity 38.9℃ (102℉)
(Smith, 1981; Harvey et al., 1981)
• The threshold duration
– At a temperature elevation of 2.0–2.5°C appears to be about 1 hr
• This dose causes NTDs and microphthalmia in 9.5-day rat embryos
(Germain et al., ’85)
• Irreversible micrencephaly in 21-day guinea pig embryos (Edwards, ’69b)
– Longer the duration of temperature elevation, the higher the risk of
teratogenic effects

12. Embryo development &
Hyperthermia

13. ANIMAL STUDIES
INTRODUCTION
Effect of maternal hyperthermia
• Hyperthermia has caused a spectrum of effects in pregnant
animals
– Type of defect caused by heat in embryos is determined
 By the developmental stage at the time of the exposure
 Severity and incidence of defects depend largely on the dose
– During the Preimplantation period
• Only a 1.5°C elevation of temperature above normal core temperature
 Embryonic death & Resorption ↑ (Bell,’87)
– After implantation
• Relatively higher doses can result in malformation
• Developmental defects have rarely been found with elevations less than 2–2.5°C

14. ANIMAL STUDIES
INTRODUCTION
Fetal developmental stage

15. ANIMAL STUDIES
INTRODUCTION
Effect of maternal hyperthermia

16. What is the mechanism?

17. MECHANISMS
How can hyperthermia damage ?
• The pathogenic effects of a damaging dose of heat at a
sensitive period include
– Interfere with protein synthesis via heat-shock proteins
 Cell death in S-phase of cell cycle by apoptosis
 NTDs
 Delay of mitotic activity in M-phase cells
 Cause vascular disruption and placental infarction
 Hypoplasia of limbs and digits, Gastroschisis
 Cranial nerve defects, neurogenic arthrogryposis, hypodactyly
 Death of embryo or severe & lethal malformations
– Heat induced uterine motility
 Expulsion of the fetus at non-viable stage of gestation

18. INTRODUCTION
MECHANISMS
How can hyperthermia damage ?
• Temporary elevation of the temperature to a level that does not cause
defects is followed in a short time by the activation of the stress response
that provides tolerance to elevations that normally cause defects
• When the heat shock response is activated, the gene activity that initiates
and controls a developmental event is abruptly suspended and embryonic
survival is achieved at the expense of normal development

19. What are the effects of
maternal hyperthermia to
embryo/fetus?

20. ANIMAL STUDIES
Effects of maternal hyperthermia
• In pregnant domestic animals, abortion is one of the most
common early manifestations of a febrile infection
• Experimentally induced malformations after hyperthermic
exposures in animals involve many organs and structures
(reviewed by Edwards, ’86; Edwards et al.,’95)
• Maternal hyperthermia during late pregnancy or during labor
has been identified as a possible risk factor for cerebral palsy
(Impey et al., 2001)

21. ANIMAL STUDIES
Effects of maternal hyperthermia
• Anencephaly/Exencephaly
• Encephalocele
• Micrencephaly
• Microphthalmia
• Cranial nerve defect
• Talipes, Arthrogryposis
• Abdominal wall defects, Limb reduction defects
• Leduced learning capacity
• Heart defects and hypodactyly
• Cataracts and coloboma
• Behavioral abnormalities
Central nervous system (CNS) defects appear to be the most
common consequence of hyperthermia in all species (Reprotox, 1996)

22. ANIMAL STUDIES
Effects of maternal hyperthermia
JOHN M. GRAHAM et al.
TERATOLOGY 58:209–221 (1998)

23. HUMAN STUDY
Hyperthermia defects
• NTDs
 Spina bifida (m/c)
 Encephalocele
 Anencephaly(severe)
– 1~2/1,000 births
– Occur when the spine or skull does
not close properly
– CNS begins to form during the third
week after conception with neural
tube closure occurring by 18-28 days
– Proportion of neural tube defects
associated with first-trimester
hyperthermia ranged from 10–14%
– Between exposure and neural tube
defects was stronger with hot tub use
than with sauna use

24. HUMAN STUDY
Hyperthermia defects
Retarded micorcephlic 11-year-old girl was exposed to 3 days of high fever (39-40°C)
during the fifth week of gestation due to maternal Hong Hong flu
She also had neurogenic talipes

25. HUMAN STUDY
Hyperthermia defects
Moebius sequence, with bilateral sixth and seventh cranial nerve palsies resuling
in paralysis of lateral gaze and immobile facial masculature
Girl: exposed to fever of 102 ℉ for 3~4 days at 18weeks postconcpetion
Boy: exposed to 3 days of high fever at 15 weeks postconception

26. Any interactions of other agents?

27. ANIMAL STUDIES
Interactions with other agents
• Some agents are known to interact positively or negatively
with hyperthermia, increasing or decreasing the incidence and
severity of defects
• Positively effect
– Agents can cause defects with usually subteratogenic doses if they are
combined with normally harmless temperature elevations
 Alchohol (Graham and Ferm, 1985; Shiota et al., 1988)
 vitamin A (Ferm and Ferm,1979)
 Arsenic (Ferm and Kilham, 1977)
 Lead (Edwards and Beatson, 1984)
 Toxemia (Hilbelink et al., 1986)
 Ultrasound (Angles et al., 1990)

28. ANIMAL STUDIES
Interactions with other agents
• Protection effect
– Agents given during the temperature elevation appear to ameliorate the
damage
 Folate (Shinand Shiota, 1999; Acs et al., 2005)
 Multivitamin supplements containing folates (Botto et al., 2002)
 Aspirin or other antipyretic agents (Suarez et al., 2004; Acs et al.,2005)

29. How to counseling?

30. SUMMUARY
Counseling
• Hyperthermia during pregnancy
– Cause embryonic death, abortion, developmental defect and growth
restriction
• Fever early in pregnancy
 NTDs are detectable during pregnancy through a combination of
ultrasound and AFP screening at approximately 15~20 weeks
 Elevated levels of AFP ; further diagnostic testing: amniocentesis or a
targeted ultrasound exam
 AFP screening in combination with a targeted ultrasound at 18-20
weeks gestation can detect the majority of babies with an open neural
tube defect

31. SUMMUARY
Counseling
• Using the Hot tub and sauna is possible?
 Bathing in hot tubs can elevate core body temperatures much more
quickly than saunas
 Hot tub or sauna use during pregnancy should be limited to less than 10
minutes
: Because it may take only 10 to 20 minutes in a hot tub or sauna to raise
your body temperature to 102 ℉(38.9°C)

32. Thank you for attention