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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