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