Teratogenesis

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Teratogenesis

• A teratogen, from the Greek root teras, meaning
  monster or marvel, is any environmental factor
  that causes a structural or functional
  abnormality in the developing fetus or embryo.
  These environmental agents include
• infections, medications, drugs, chemicals,
  maternal metabolites, such as phenylalanine or
  mechanical forces.(1-2)

2
Effects of drugs on the fetus (2)

• the first week after fertilization is the period
  of the zygote. During this time the most common
  adverse effect of drugs is the termination of
  pregnancy , which may occur before the woman even
  knows that she is pregnant.
• The second to the eighth week of gestation is
  period of the embryo. It is mainly during this
  period of organogenesis that drugs produce
  dramatic and catastrophic structural
  malformations.

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terminology

• Malformation(3)
• A primary structural defect arising from a
  localized error in morphogenesis. (cardiac septal
  defects)
• Deformation
• An alteration in shape or structure of a part
  that has differentiated normally. (mostly
  involving musculoskeletal system and are probably
  caused by intrauterine molding, like various
  forms of clubfoot and congenital hip dislocation)
• Disruption
• A structural defect resulting from destruction of
  a previously normally formed part. two mechanisms
  are involved
• 1-entanglement followed by tearing apart or
  amputation (like amniotic bands)
• 2-interruptioin of blood supply to a developing
  part, leading to infarction, necrosis or
  resorption of structure distal to the insult.
  (like jejunoileal atresia and gastroschisis)
• Dysplasia
• An abnormal organization of cells and the
  structural consequences.
• ( localized like hemangioma, generalized like
  connective tissue disorders)

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drug Effect on fetus and neonate
Accutane ) isotretinoin ) Facial-ear anomaly, heart defect, CNS anomaly
alcohol Congenital cardiac, CNS, limb anomalies
carbamazepine Spina bifida
Carbon monoxide Cerebral atrophy, microcephaly, seizure
Cocaine/crack Microcephaly, LBW, IUGR
misoprostol Arthrogryposis, cranial neuropathies, equinovarus
phenytoin neuroblastoma
Warfarin (coumadin) Fetal bleeding and death, hypoplastic nasal structures
penicillamine Cutis laxa syndrome
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MATERNAL MEDICATION AND TOXIN EXPOSUREAND THE
FETUS(3)

• The effects of drugs taken by the mother vary
  considerably, especially in relation to the time
  in pregnancy when they are taken and the fetal
  genotype for drug metabolizing enzymes.
• Miscarriage or congenital malformations result
  from the maternal ingestion of teratogenic drugs
  during the period of organogenesis.
• Maternal medications taken later, particularly
• during the last few weeks of gestation or during
  labor, tend to affect the function of specific
  organs or enzyme systems, and they adversely
  affect the neonate rather than the fetus .

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Diagnosis time

• The effects of drugs may be evident immediately
  in the delivery room or later in the neonatal
  period, or they may be delayed even longer.
• The administration of diethylstilbestrol during
  pregnancy has resulted in vaginal adenosis and
  vaginal adenocarcinoma in females in the 2nd or
  3rd decade. In addition to in utero
  carcinogenesis, various reproductive problems
  have been reported in these women, including
  cervical anomalies and premature births, ectopic
  pregnancies, and spontaneous pregnancy loss.

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Impact of genetic

• Evidence has confirmed an interaction between
  genetic factors and susceptibility to certain
  drugs or environmental toxins.
• Phenytoin teratogenesis may be mediated by
  genetic differences in the enzymatic production
  of epoxide metabolites specific genes may
  influence the adverse effects of benzene exposure
  during pregnancy.
• Growth-restricting effects of smoking on the
  fetus is influenced by
• polymorphisms of genes encoding enzymes that
  metabolize the polycyclic aromatic hydrocarbons
  in cigarette smoke .

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Drug use in pregnancy

• Often the risk of controlling maternal disease
  must be balanced with the risk of possible
  complications in the fetus.
• The majority of women with epilepsy have normal
  fetuses. Nonetheless, several commonly used
  antiepileptic drugs (AEDs) are associated with
  congenital malformations.
• Infants exposed to valproic acid may have
  multiple anomalies including neural tube defects,
  hypospadias, facial anomalies, cardiac anomalies,
  and limb defects. In addition, they have lower
  developmental index scores compared to those
  unexposed infants or those exposed to other
  commonly used AED.

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Radiation(3)

• Accidental exposure of pregnant women to
  radiation is a common cause for anxiety about
  whether the fetus will have birth defects or
  genetic abnormalities. It is unlikely that
  exposure to diagnostic radiation will cause gene
  mutations no increase in genetic abnormalities
  has been identified in the offspring exposed as
  unborn fetuses to the atomic bomb explosions in
  Japan in 1945.

10
Maximum safe dose of radiation in pregnancy

• The recommended occupational limit of maternal
  exposure to radiation from all sources is 500
  mrad for the entire 40 wk of a pregnancy.
• The limited data on human fetuses show that large
  doses of radiation (20,000-50,000 mrad) are
  harmful to the central nervous system, as
  evidenced by microcephaly, mental retardation,
  and IUGR. Leukemia is another risk.
• Therapeutic abortion is often recommended when
  exposure exceeds 10,000 mrad.
• It is more likely that a human fetus will be
  exposed to 1,000-3,000 mrad, an amount not shown
  to cause malformations. Whether this level of
  fetal exposure is associated with an increased
  risk for childhood cancer or leukemia is
  controversial.

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Maternal PKU

• Mental retardation, hypertonia, low birth weight,
  microcephaly, cardiac defects, spontaneous
  abortion.

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Multiple malformation vs sequence

• The pattern of multiple anomalies that occurs
  when a single primary defect in early
  morphogenesis produces multiple abnormalities
  through
• a cascading process of secondary and tertiary
  errors in morphogenesis
• is called a sequence.
• When evaluating a child with multiple anomalies,
  the physician must differentiate multiple
  anomalies secondary to a single localized error
  in morphogenesis (a sequence) from a multiple
  malformation syndrome. In the former, recurrence
  risk counseling for the multiple anomalies
  depends entirely on the risk of recurrence for
  the single localized malformation.
• The Robin malformation sequence is a pattern of
  multiple anomalies produced by mandibular
  hypoplasia. Because the tongue is relatively
  large for the oral cavity, it drops back
  (glossoptosis), blocks closure of the posterior
  palatal shelves, and causes a V-shaped cleft
  palate. There are numerous causes of mandibular
  hypoplasia, all of which result in characteristic
  features of Robin sequence.

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Fetal alcohol syndrome

1. Prenatal onset and persistence of growth
   deficiency for weight, length, and head
   circumference.
2. Facial abnormalities including short palpebral
   fissure, epicanthal folds, maxillary hypoplasia,
   micrognathia, and thin upper lips.
3. Cardiac defects, primarily septal defects.
4. Minor joint and limb abnormalities including some
   restriction in movements and altered palmar
   crease pattern.
5. Delayed development and mental deficiency varying
   from borderline to severe.

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Cigarette smoking Low birth weight
danazole virilization
hyperthermia Spina bifida
lithium Ebsteins anomaly, macrosomia
methyltestosterone Masculinization of female fetus
Methyl mercury Minamata disease
Prednisolone Cleft palate and lip
progesterone Masculinization of female fetus
Vitamin D Supravalvular aortic stenosis, hypercalcemia
misoprostol Arthrogryposis, cranial neuropathies equinovarus
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amiodarone Bradycardia, hypothyroidism
Anesthetic agents (volatile) CNS depression
Aspirin Neonatal bleeding
Captopril Transient anuric renal failure, oligohydramnios
Dexamethasone Periventricular leukomalacia
fluoxetine Transient neonatal withdrawal, hypertonicity
Oxytocin Hyperbilirubinemia, hyponatremia
isoxsuprine Ileus, hypoglycemia, hypocalcemia, hypotension
Pyridoxine seizure
sulfonylurea Refractory hypoglycemia
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• References
• Avery 2005
• Fanarof 2006
• Nelson 2004