hyperthermia2 in pregnancy/이민영
TRANSCRIPT
Hyperthermia in pregnancy
2013.4.9.
주산기 전임의 이민영
Heat?
INTRODUCTION
• 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
Normal body temperatures
INTRODUCTION
• 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)
Dinurial variation
INTRODUCTION
• 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
What is hyperthermia?
Hyperthermia
INTRODUCTION
• 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
Fever VS hyperthermia??
What are differences?
INTRODUCTION INTRODUCTION
Fever Hyperthermia
Change in hypothalamic set
point
Failure in thermoregulation
Involves cytokines Can exceed >41℃
Diurnal variation Can be detrimental
Rarely exceeds 41℃ Absence of diurnal variation
Complications are rare
Hyperthermia & Pregnancy
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)
INTRODUCTION ANIMAL STUDIES
• 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
• 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
INTRODUCTION ANIMAL STUDIES
Teratogenecity
In humans, threshold temperature for teratogenicity 38.9℃ (102℉)
(Smith, 1981; Harvey et al., 1981)
Embryo development & 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
INTRODUCTION ANIMAL STUDIES
Effect of maternal hyperthermia
INTRODUCTION ANIMAL STUDIES
Fetal developmental stage
INTRODUCTION ANIMAL STUDIES
Effect of maternal hyperthermia
What is the mechanism?
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
MECHANISMS
• 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
INTRODUCTION
How can hyperthermia damage ?
MECHANISMS
What are the effects of maternal hyperthermia to
embryo/fetus?
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)
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
ANIMAL STUDIES
Central nervous system (CNS) defects appear to be the most
common consequence of hyperthermia in all species (Reprotox, 1996)
Effects of maternal hyperthermia
ANIMAL STUDIES
JOHN M. GRAHAM et al. TERATOLOGY 58:209–221 (1998)
Hyperthermia defects
HUMAN STUDY
• 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
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
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
HUMAN STUDY
Any interactions of other agents?
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)
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)
ANIMAL STUDIES
How to counseling?
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
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)
SUMMUARY
Thank you for attention