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hyperthermia2 in pregnancy/이민영 hyperthermia2 in pregnancy/이민영 Presentation Transcript

  • Hyperthermia in pregnancy 2013.4.9. 주산기 전임의 이민영
  • INTRODUCTIONHeat? • 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
  • INTRODUCTIONNormal body temperatures • 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)
  • INTRODUCTIONDinurial variation • 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?
  • INTRODUCTIONHyperthermia • 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??
  • INTRODUCTION INTRODUCTIONWhat are differences? Fever Hyperthermia Change in hypothalamic set Failure in thermoregulation point Involves cytokines Can exceed >41℃ Diurnal variation Can be detrimental Rarely exceeds 41℃ Absence of diurnal variation Complications are rare
  • Hyperthermia & Pregnancy
  • ANIMAL STUDIES INTRODUCTIONWhy 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)
  • ANIMAL STUDIES INTRODUCTIONTeratogenecity • 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 In humans, threshold temperature for teratogenicity 38.9℃ (102℉) (Smith, 1981; Harvey et al., 1981) • 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
  • Embryo development & Hyperthermia
  • ANIMAL STUDIES INTRODUCTIONEffect of maternal 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
  • ANIMAL STUDIES INTRODUCTIONFetal developmental stage
  • ANIMAL STUDIES INTRODUCTIONEffect of maternal hyperthermia
  • What is the mechanism?
  • MECHANISMSHow 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
  • INTRODUCTION MECHANISMSHow can hyperthermia damage ? • 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
  • What are the effects ofmaternal hyperthermia to embryo/fetus?
  • ANIMAL STUDIESEffects 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 STUDIESEffects 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 Central nervous system (CNS) defects appear to be the most common consequence of hyperthermia in all species (Reprotox, 1996)
  • ANIMAL STUDIESEffects of maternal hyperthermia JOHN M. GRAHAM et al. TERATOLOGY 58:209–221 (1998)
  • HUMAN STUDYHyperthermia defects • 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
  • HUMAN STUDYHyperthermia 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 STUDYHyperthermia 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
  • Any interactions of other agents?
  • ANIMAL STUDIESInteractions 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 STUDIESInteractions 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)
  • How to counseling?
  • SUMMUARYCounseling • 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
  • SUMMUARYCounseling • 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)
  • Thank you for attention