hyperthermia and pregnancy
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Hyperthermia in Pregnancy
전임의 육지형
Definition and cause of hyperthermia
Definition
• Abnormally high body temperature: at least 38.3 ºC (101ºF) or higher
• Normal body temperature : 37ºC (98.6ºF)
Cause
Fever due to viral or bacterial infections
Hot tubs or very hot baths
Saunas
Electronic blankets
Heavy exercise on hot and humid environments
(longer than 10 minutes)
INTRODUCTION
Maternal Hyperthermia
• Shown to be a potent teratogen in experimental animals (Edwards, 1986)
Teratogen in humans (Shepard, 1992)
Character & intensity of teratogenic response
• Stage of embryonic development at the time of exposure
• Degree of temperature elevation, and its duration
Abortions (higher temperature and/or longer duration)
Embryonic death and resorption (lower elevations)
Teratogenically induced anomalies (lower elevations at critical
stages of development)
In humans, threshold temperature for teratogenicity : 38.9 ºC (102ºF)
INTRODUCTION
Teratogenic range of body temperature
• Threshold elevation capable of causing defects: 2.0-2.5 ºC
• Threshold duration at a temperature elevation of 2.0-2.5 ºC: 1 hour
• Sensitivity to maternal hyperthermia
– Pre-implantation period
• Only a 1.5 ºC elevation of temperature above normal core
temperature can result in increased rates of embryonic death
and resorption
– After implantation
• Relatively higher doses can result in embryonic and fetal death,
followed by resorption or abortion
ANIMAL STUDY
Defects induced by hyperthermia
• In experimental ANIMALS
Anencephaly/exencephaly, encephalocele
Micrencephaly
Microphthalmia
Cranial nerve defects
Reduced learning capacity and behavioral abnormalities
Talipes, arthrogryposis multiplex congenita, kyphoscoliosis
Heart defects , renal anomalies
Limb reduction defects, hypodactyly, dental agenesis
Abdominal wall defects, exomphalos
Cataracts, coloboma
ANIMAL STUDY
Three periods of prenatal development in human
DEVELOPMENT
Pre-implantation period (∼3 weeks)
• Increased pre-implantation loss due to failure to implantation
or embryonic death
Period of major organogenesis (3∼8 weeks)
• Especially, susceptible to the induction of developmental defect
• CNS, skeletal, neuromuscular, and cardiac defect
Fetal periods (8∼ weeks)
• Results mainly in reduced growth & functional defects
Clinical findings in experimental hyperthermia
compared with observations in exposed humans
DEVELOPMENT
Mechanisms of Defects by hyperthermia
Apoptotic cell death
• NTD, microencephaly
Disturbance of neural crest cell and neuronal cell migration
• Defects in heart and face, Hirschsprung disease, ectopic nests of
neurons in the brain
• Behavioral deficits and reduction in IQ
Damage to cell membrane
Damage to blood vessels & placenta
• Hypoplasia of limbs & toes(hypodactyly), exomphalos , gastroschisis,
Moebius syndrome, neurogenic arthrogryposis, possibly abortion and
fetal growth restriction
MECHANISMS
Fetal temperature ; 0.6 ºC higher than that of mother
• Almost no ability to regulate its own temperature
• Determined primarily by maternal temperature & placental blood flow
Pathways for the heat transfer
• Umbilical circulation
generally thought to eliminate the bulk (85%) of fetal heat
• Fetal skin, amniotic fluid, and uterine wall
During extended periods of hyperthermia
• Reduced blood flow to uterus and placenta
• Contribute to reduction in placental and fetal body weight
• Significance of these effect in teratogenesis is not clear
Maternal-fetal heat exchange
MECHANISMS
Sufficient (threshold) dose of heat can cause defective development
especially during sensitive periods of organogenesis
Once susceptible periods has passed (after organ formed), the organ is
relatively resistant to heat effect
Stage of embryonic and fetal susceptibility to heat closely resemble to
ionizing radiation
In pre-implantation stages
• Before organs begin to form
• Heat can cause embryonic death, but malformations are rare
Critical Periods (I)
MECHANISMS
In early embryo stages
• Neural plate and neural tube stages
• Neural tube, eye, face, heart, and vertebral formation
• Embryo is susceptible to damage of heat
• Brain : anencephaly, exencephaly, spina bifida and encephalocele
• Eyes : anophthalmia, microphthalmia and defects of the iris
• Face : small upper or lower jaws, cleft of the face
• Heart
• After neural tube closes to form the brain and spinal cord
• Vertebrae and ribs become susceptible to damage
Critical Periods (II)
MECHANISMS
In mid- to late embryonic stages
• Neurogenesis and development of body structure
• If hyperthermia in this stage irreversible cell death
• Affecting all regions of the brain and leading to microencephaly
• Other defects
• Clubfoot (talipes) associated with defective spinal cord development
• Small or missing toes
• Tooth defect
• Abdominal wall defects (umbilical hernia)
• Eye defect : cataract, coloboma (split iris) and blindness
• Learning problem and seizure
Critical Periods (III)MECHANISMS
microencephaly
In fetal stages
• Further brain development can be retarded by heat
• Irreversible reduction in brain size and function
• Loss of motor neuron in the spinal cord
• Development of arthrogryposis with rigidity
of joints and atrophy of muscles
• Moebious sequence
• Neurologic disorder with loss of neurons in the brain stem nuclei
• Leading to paralysis of a number of the cranial nerves
• Frequently associated with distal limb reduction defects such as
- Poland’s sequence
(sporadic unilateral distal limb and pectoralis major deficiency)
- Oromandibular-limb hypogenesis
(sporadic distal limb, tongue, and pectoralis major deficiency)
Critical Periods (IV)MECHANISMS
Hyperthermia in humans by hot tub and sauna
Milunsky et al.,1992
• Proportion of NTDs associated with first-trimester hyperthermia ranged
from 10-14%
• Relationship between exposure and NTDs was stronger with hot tub use
than with sauna use
• Exposure to multiple heat sources was associated with an greater risk
for NTDs
Harvey et al., 1981
• Measured vaginal temperatures of 20 non-pregnant women while in hot
tubs and saunas
• It took 10 min in a 41.1°C hot tub, and 15 min in a 39°C hot tub, for
vaginal temperature to reach 38.9°C, and none of the 20 women were
able to remain in the 81.4°C sauna long enough for their temperatures
to reach 38.9°C.
HUMAN STUDY
Spraget and Fraser, 1982
• A study of 50 Canadian women indicated that 20 women were able to remain
in a sauna set at 93.3–98.8°C for 20 min, resulting in their mean oral body
temperatures reaching 38.9°C
Ridge and Budd, 1990
• A study of 24 Australian women revealed they were also able to remain in a
hot tub set at 40°C until their temperatures reached 39°C, with 54% of the
subjects not feeling uncomfortably hot
HUMAN STUDY
Subjective feeling of being ‘‘overheated’’ may not be enough to protect
all women from teratogenic exposures to heat in saunas and hot tubs.
For potentially pregnant women using hot tubs set at 40°C, exposure
ought to be limited to no more than 10 min, while exposure in sauna
set above 90°C ought to be limited to a maximum of 15 min
Chambers et al., 1997
• Followed a cohort of 301 pregnant women who called the California
Teratogen Information Service with concerns regarding a fever during
pregnancy
• The high-fever group: contained 126 women who reported a fever of
102°F(38.9ºC) or above for at least 24 hr
• The low-fever group: fever of less than 102°F for any length of time, or a
fever of 102°F or above for less than 24 hr
• Compared to a control group of 273 similarly ascertained women exposed
to non-teratogens, women in the high-fever group demonstrated a
significantly increased rate of major malformations (6/38 or 15.8%) in
comparison with the control group (11/242 or 4.5%)
HUMAN STUDY
Hyperthermia by fever during pregnancy
Chambers et al., 1997 (continued)
• These malformations included one case of transposition of the great
vessels and two cases of anencephaly
• Among 25 liveborn children in the high-fever group, 6 had 3 or more
minor malformations, including cleft uvula in 3, short palpebral fissures in
2, and preauricular pit or tag in 2.
This supported the hypothesis that hyperthermia at or above 102°F(38.9ºC)
for more than 24 hr in the first 4 weeks after conception may affect both
brain and facial morphogenesis in the human
HUMAN STUDY
Pleet et al., 1981
• Among 28 dysmorphic infants exposed to hyperthermia between 4–14
weeks of gestation, all survivors had mental deficiency, and most had
altered muscle tone(usually hypotonia with increased deep tendon reflexes)
• Those exposed at 4–7 weeks had an increased prevalence of facial defects,
and in 3 of the 28 pregnancies the hyperthermia was due to a long stay in
a hot tub or sauna
• The types of facial defects observed included midface hypoplasia, cleft lip
and/or palate, micrognathia, microphthalmia, and external ear anomalies
HUMAN STUDY
Hyperthermia by fever during pregnancy
Hyperthermia by fever during pregnancy
HUMAN STUDY
Profoundly retarded microcephalic 11-year-old girl was exposed to 3 days of high fever (39–40°C) during the 5th week of gestation due to maternal Hong Kong flu. She also had neurogenic talipes
Mentally retarded 12-year-old girl was exposed to 2 weeks of sustained fever (38–39°C) between weeks 6–8 of gestation due to maternal viral laryngotracheitis. She had hypotonic diplegia with neurogenic talipes, ear anomalies, congenital heart defect, cleft palate, and micrognathia.
Spragget and Fraser, 1982
• Microphthalmia has been associated with febrile first-trimester illnesses
also with hypospadias and cardiac defects
Erickson, 1991
• Reported associations between fever and/or flu and the occurrence of
neural tube defects, nervous system defects, gastrointestinal defects, cleft
lip and/or palate, defective cardiac valves, and diaphragmatic hernias
Little et al., 1991
• Confirmed an association between the occurrence of abdominal wall defects
and maternal report of fever of 101°F or higher for 24 hr or more during
the first trimester
Lipson, 1988
• Reported an association between first-trimester hyperthermia and
Hirschsprung disease
HUMAN STUDY
McDonald, 1961
• In a prospective study of 3,144 pregnancies
• Reported that the prevalence of major congenital anomalies and abortions
was significantly increased in women who experienced a febrile illness or
pulmonary tuberculosis during the first 12 weeks of pregnancy
• Among 27 women who worked in a hot laundry environment during
pregnancy, 4 had children with a major defect (anencephaly, hydrocephalus,
congenital heart defect, and hypospadias)
• When the febrile illness occurred between weeks 5–8, noted the greatest
incidence of congenital anomalies
HUMAN STUDY
Hyperthermia by fever during pregnancy
Kline et al., 1985
• Confirmed a significant association between fever during pregnancy and
spontaneous abortion
• Some febrile episodes resulting in fetal death and expulsion 6–8 weeks
later, while other febrile episodes resulted in immediate uterine
contractures with expulsion of a previable fetus
Coffey and Jessop, 1963
• Viral infections are a common cause of fever
• Epidemics of influenza have been associated with an increased occurrence
of malformations, most of which affect the central nervous system,
particularly neural tube defects
HUMAN STUDY
Moebius syndrome
• Consists of congenital facial palsy (seventh cranial nerve)
combined with lateral rectus palsy (sixth cranial nerve),
in association with other cranial nerve, brain-stem,
and musculoskeletal problems
Oromandibular-limb hypogenesis syndrome
• Sporadic distal limb, tongue, and jaw hypoplasia
Amyoplasia-type arthrogryposis
• Result from ischemia to the fetal spinal cord
HUMAN STUDY
Fetal vascular disruption in maternal fever
Moebius syndrome
Oromandibular-limb hypogenesis syndrome
Amyoplasia-type arthrogryposis
Govaert et al., 1989
• Reported the case of Moebius syndrome with prenatal ischemic necrosis
and brain-stem calcifications, was associated with a flu-like first-trimester
illness
Graham et al., 1988
• Reported 5 cases of Moebius syndrome associated with various febrile
illnesses occurring between 8–22 weeks of gestation, as well as 8 other
children with cortical atrophy, microcephaly, and/or abnormalities of the
corpus callosum, whose mothers gave histories of second- trimester febrile
illnesses
HUMAN STUDY
Fetal vascular disruption in maternal fever
Superneau and Wertelecki, 1985
• Reported 2 children with oromandibular-limb hypogenesis syndromes
whose mothers had febrile illnesses at either 8 weeks or 10–11 weeks of
gestation
Edwards et al., 1990
• Reported 2 children with the amyoplasia type of arthrogryposis and
maternal spikes of fever and chills between 8 weeks and term at about
2-week intervals
HUMAN STUDY
Summary
Hyperthermia during pregnancy
• Cause embryonic death, abortion, developmental defect and growth
restriction
In humans,
• Elevation of maternal body temperature by 2 ºC at least 24hr can
cause a range of developmental defects
• But, there is little information on thresholds for shorter exposures
Further experimental and epidemiological studies are recommended
SUMMARY
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