Hyperthermia during pregnancy can cause developmental defects in embryos and fetuses. A body temperature of at least 38.3°C or higher is considered hyperthermia. Critical periods of susceptibility are during the first 8 weeks of pregnancy when organogenesis occurs. Hyperthermia has been associated with defects of the brain, heart, limbs and facial structures in both animal and human studies. Sustained fevers over 38.9°C for more than 24 hours during the first trimester appear to increase the risk of birth defects in humans. Strict limits on hot tub and sauna use are recommended during early pregnancy to avoid hyperthermia.

1. Hyperthermia in Pregnancy
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2. INTRODUCTION
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)

3. 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)

4. ANIMAL STUDY
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

5. 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

6. DEVELOPMENT
Three periods of prenatal development in human
 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

7. DEVELOPMENT
Clinical findings in experimental hyperthermia
compared with observations in exposed humans

8. MECHANISMS
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

9. MECHANISMS
Maternal-fetal heat exchange
 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

10. MECHANISMS
Critical Periods (I)
 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

11. MECHANISMS
Critical Periods (II)
 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

12. MECHANISMS
Critical Periods (III)
 In mid- to late embryonic stages
microencephaly
• 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

13. MECHANISMS
Critical Periods (IV)
 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)

14. HUMAN STUDY
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.

15. 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
 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

16. HUMAN STUDY
Hyperthermia by fever during pregnancy
 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%)

17. HUMAN STUDY
 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

18. HUMAN STUDY
Hyperthermia by fever during pregnancy
 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

19. HUMAN STUDY
Hyperthermia by fever during pregnancy
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.

20. HUMAN STUDY
 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

21. HUMAN STUDY
Hyperthermia by fever during pregnancy
 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

22. HUMAN STUDY
 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

23. HUMAN STUDY
Fetal vascular disruption in maternal fever
Moebius syndrome
 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
 Oromandibular-limb hypogenesis syndrome
• Sporadic distal limb, tongue, and jaw hypoplasia
 Amyoplasia-type arthrogryposis Amyoplasia-type arthrogryposis
• Result from ischemia to the fetal spinal cord

24. HUMAN STUDY
Fetal vascular disruption in maternal fever
 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

25. HUMAN STUDY
 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

26. SUMMARY
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

27. Thank you