Workshop on Pharmacology of hearing and speech sciences

1. DRUGS IN PREGNANCY

2. During embryogenesis-drugs
&chemicals may adversely affect
development

4. Teratology
 Teratology
 Science that studies the causes of abnormal
development
 The term is derived from the Greek “teratos” which
means monster
 Birth defects is the number one cause of infant
mortality

5. Critical Periods

6. Congenital Malformations
 Causes
 Genetic/chromosomal
 Enviornmental
 Incidence
 2-3% of newborn (4-6% by age 5)
 In 40-60% of all birth defects cause is unknown
 Genetic/chromosomal
 10%-15%
 Environmental
 10%
 Multifactorial (genetic & environmental)
 20%-25%

7. The issues
 Only half of all pregnancies are planned
 Many women need medications for pregnancy
induced conditions e.g.
 Morning Sickness,
 Chronic conditions (e.g. Epilepsy)
 Intercurrent conditions (Allergies)
 Diabetes
 Hypertension
 Women work with chemicals, exposed to
radiation and use illicit drugs

8.  Even when exposed to non teratogenic drugs-
women assign 25% teratogenic risk (Am J
Obstet Gynecol 1989)
 Evidence-based counseling can prevent
unnecessary pregnancy terminations
(Teratology 1990)
Misperception and Pregnancy
Terminations

9.  Following the Chernobyl disaster-half of all
pregnancies in Athens were terminated
(Trichopolous, BMJ, 1985)
 Women exposed to diagnostic radiation assign
major teratogenic risk (Bentur, Teratology,
1991)

10. Nausea and Vomiting of Pregnancy
(NVP)
• NVP affects 80% of pregnant women
*Bendectin (doxylamine-pyridoxine) was used by
40% pregnant American women in 1978
*Due to litigations-drug removed in 1983 despite
scientific/FDA support
*In Canada: Diclectin use is increasing-Temporal
decrease in hospitalizations

11. U.S.A. Temporal Trends forU.S.A. Temporal Trends for
Limb Reduction Deformities, Bendectin Sales,Limb Reduction Deformities, Bendectin Sales,
and Hospitalizations for NVPand Hospitalizations for NVP

12. Depression in Pregnancy
*Affects up to 20% of pregnant women
* SSRI appear safe (both dyspmorphology
&neurobehavior)
(Nulman et al 1996, 2002)
* Those treated-very low average doses (Nulman 2003)
SSRI: Selective serotonin reuptake inhibitor

13. Hypoglycemics
 Fear: Oral hypoglycemics cross placenta-neonatal
hypoglycemia
 Elliott (Am J Obstet Gynecol 1994): Glyburide does not
cross the placenta in perfusion studies.
 Langer et al (NEJM 2001):
Glyburide as effective and safe as insulin
Undetectable umbilical cord levels with therapeutic
maternal levels(50-150ng/ml)

14. Fetal Safety of Oral Hypoglycemics
 10 studies
 471 exposed;1,344 controls
 Major malformations: OR 1.05 (.65-1.7)
 Neonatal death: OR1.16(.67-2)
(Can J Clin Pharmacol 2003;10:179-83)

15. Major Medicinal Teratogens
 Antiepileptics
 Carbamazepine- NTD(1%) – Neural tube defects
 Valproate- NTD(2%);other malformations
(Holmes 2003)
 Phenytoin: Fetal Hydantoin Syndrome(10-
15%?)
 ACE inhibitors: Renal insuffuciency, hypocalvaria
 Lithium- Ebstein’s anomaly(1/5000)

16. Chemical agents/Drugs
 Role of chemical agents & drugs in production of
anomalies is difficult to assess
 Most studies are retrospective
 Relying on mother’s memory
 Large # of pharmaceutical drugs used by pregnant
women
 NIH study – 900 drugs taken by pregnant women
 Average of 4/woman during pregnancy
 Only 20% of women use no drugs during pregnancy
 Very few drugs have been positively identified as
being teratogenic

17. Drugs
 Thalidomide
 Antinauseant & sleeping pill
 Found to cause
 Total or partial absence of the extremities
 Intestinal atresia
 Cardiac abnormalities
 Many women had taken thalidomide early in
pregnancy

18.  Aminopterin
 Antagonist of Folic Acid
 Antineoplastic agent which inhibits mitosis
 Defects
 Anencephaly
 Meningocele
 Hydrocephalus
 Cleft lip & palate

19.  Anticonvulsants (to treat epilepsy)
 Diphenylhydantoin (phenytoin)
 Craniofacial defects
 Nail & digital hypoplasia
 Growth abnormalities
 Mental deficiency
 The above pattern is know as “fetal hydantoin
syndrome”
 Valproic acid
 Neural tube defects
 Heart defects
 Craniofacial & limb anomalies

20.  Trimethadione (syndrome)
 Malformed ears
 Cleft palate
 Cardiac defects
 Urogenital anomalies
 Skeletal anomalies

21.  Antipsychotic drugs (major tranquilizers)
 Phenothiazine & lithium
 Suspected teratogenic agents
 Antianxiety drugs (minor tranquilizers)
 Meprobamate, chlordiazepoxide,
 Severe anomalies in 11-12% of offspring where
mothers were treated with the above compared to 2.6%
of controls
 diazepam (valium)
 Fourfold ⇑ in cleft lip with or without cleft palate

22.  Anticoagulants
 Warfarin
 Teratogenic
 Hypoplasia of nasal cartilage
 Chondrodysplasia
 Central nervous system defects
 Mental retardation
 Atrophy of the optic nerves
 Antihypertensive agents
 angiotensin converting enzyme (ACE) inhibitor
 Growth dysfunction, renal dysfunction, oliogohydramnios,
fetal death

23.  Propylthiouracil
 Goiter
 Mental retardation
 Potassium iodide
 Goiter
 Mental retardation
 Streptomycin
 deafness
 Sulfonamides
 kernicterus
 Imipramine (antidepr.)
 Limb deformaties
 Tetracyclines
 Bone & tooth
anomalies
 Amphetamines
 Oral clefts
 CV abnormalities
 Quinine
 Deafness
 Aspirin
 Potentially harmful in
large doses

24.  Isotretinoin
 Analogue of vitamin A
 Drug is prescribed for treatment of cystic acne &
other chronic dermatoses
 Highly tertogenic
 Reduced & abnormal ear development
 Flat nasal bridge
 Cleft palate
 Hydrocephaly
 Neural tube defects
 Heart anomalies

25. Recreational drugs
 PCP angel dust
 Possible malformations & behavioral disturbances
 Cocaine-vasoconstrictor ⇒ hypoxia
 Spontaneous abortion
 Growth retardation
 Microcephaly
 Behavioral problems
 Urogenital anomalies
 gastroschisis
X

27. Alcohol
 Relationship between alcohol consumption &
congenital abnormalities
 Fetal alcohol syndrome
 Craniofacial abnormalities
 Short palpebral fissures
 Hypoplasia of the maxilla
 Limb deformities
 Altered joint mobility & position
 Cardiovascular defects
 Ventricular septal abnormalites
 Mental retardation
 Growth deficiency

28. Cigarette Smoking
 Has not been linked to major birth defects
 Smoking does contribute to intrauterine growth
retardation & premature delivery
 Some evidence that is causes behavioral
disturbances

29. Hormones
 Androgenic Agents
 Synthetic progestins were used frequently to prevent
abortion
 Ethisterone & norethisterone
 Have considerable androgenic activity
 Masculinization of female genitalia
 Diethylstilbesterol
 Commonly used in the 1940’s & 1950’s to prevent
abortion; in 1971 determined that DES caused
increased incidence of vaginal & cervical cancer in
women who had been exposed to DES in utero
 In addition high % suffered from reproductive
dysfunction
 Oral Contraceptives
 Low teratogenic potential, discontinue if pregnancy
X

30. Maternal Disease
 Disturbances in metabolism (diabetic mothers)
 High incidence of stillbirth, neonatal deaths
 Abnormally large infants
 Congenital malformations
 ⇑ risk 3-4X
 Cardiac, Skeletal, CNS Anomalies
 Caudal dysgensis
 Partial or complete agenesis of sacral vertebrae in
conjuction with hindlimb hypoplasia
 Hypoglycemic episodes ⇒teratogenic Oral
hypoglycemic agents ⇒ maybe teratogenic
X

31.  Phenylketonuria (PKU)
 Enzyme phenylalanine hydroxylase is deficient ⇑
phenylalanine (PA) concentrations
 Mental retardation
 Microcephaly
 Risk can be ⇓ with low PA diet
X

32. Hypoxia
 Associated with congenital malformations in a
great variety of experimental animals
 In humans ???
 Maybe smaller babies e.g. offspring at high altitude
X

33. Environmental Chemicals
 Mercury
 Fish, seed corn sprayed with mercury containing
fungicide
 Multiple neurological symptoms
 Lead
 ⇑ abortions
 Growth retardation
 Neurological disorders
X

34. Conclusions
 Pregnant and lactating women are commonly
orphaned from the benefits of drug therapy, even
when solid data on safety/effectiveness exist.
 If “Safe use of a drug in pregnancy has not been
established. It should not be administered to
women of childbearing age unless, in the opinion
of the treating physician, the expected benefits to
the patient markedly outweigh the possible
hazards to the child or fetus”.
 Change labeling system
 Allow evidence-based counseling
 Always consider the risk of untreated maternal
condition

35. Infectious Agents
 Rubella (German Measles)
 Malformations of the eye
 Cataract (6th
week)
 Microphthalmia
 Malformations of the ear (9th
week)
 Congenital deafness
 Due to destruction of cochlea
 Malformations of the heart (5th
-10th
week)
 Patent ductus arteriosis
 Atrial septal defects
 Ventricular septal defects
X
X

36. Infectious Agents (cont.)
 Rubella (German measles)
 May be responsible for some brain abnormalities
 Mental retardation
 Intrauterine growth retardation
 Myocardial damage
 Vascular abnormalites
 Incidence
 47%- during 1st
four weeks
 22% - 5th
– 8th
weeks
 13% - 9th
– 16th
week
X

37. Infectious Agents (cont.)
 Rubella (cont.)
 Lab tests permit detection of virus
 Antibody levels can be determined
 In one study 85 % of women tested were immune
(n = 600)
 Virus infects fetus via the placenta
 Infection of the child may persist after birth for a
number of years
 Infection can be transmitted to hospital personnel
 Vaccines are considered safe & effective
X

38. Infectious Agents (cont.)
 Cytomegalovirus
 Disease is often fatal early on
 Malformations
 Microcephaly
 Cerebral calcifications
 Blindness
 Chorioretinitis
 Kernicterus (a form of jaundice)
 multiple petechiae of skin
 Hepatosplenomegaly
 Mother asymptomatic
X

39. Infectious Agents (cont.)
 Herpes Simplex Virus
 Intrauterine infection of fetus occasionally occurs
 Usually infection is transmitted close to time of
delivery
 Abnormalities (rare)
 Microcephaly
 Microphthalmos
 Retinal dysplasia
 Hepatosplenomegaly
 Mental retardation
 Usually child infected by mother at birth
 Inflammatory reactions during first few weeks
X

40. Infectious Agents (cont.)
 Varicella (chickenpox)
 Congenital anomalies
 20% incidence following infection in 1st
trimester
 Limb hypoplasia
 Mental retardation
 Muscle atrophy
 HIV/AIDS
 Microcephaly
 Growth retardation
 Abnormal facies (expression or appearance of the
face) X

41. Infectious Agents (cont.)
 Toxoplamosis
 Protozoa parasite (Toxoplama gondii)
 Sources
 Poorly cooked meat
 Domestic animals (cats)
 Contaminated soil with feces
 Syphilis
 Congenital deafness
 Mental retardation
 Diffuse fibrosis of organs (eg. liver & lungs)
 In general most infections are pyrogenic
 Hyperthemia can be teratogenic
 Fever
 Hot tubs & Saunas

42. Radiation
 Teratogenic effect of ionizing radiation well
established
 Microcephaly
 Skull defects
 Spina bifida
 Blindness cleft palate
 Extremity defects
 Direct effects on fetus or indirect effects on
germ cells
 May effect succeeding generations
 Avoid X-raying pregnant women

43. Radiation
 Studies of offspring of Japanese women who
were pregnant at the time of the atomic bomb
explosions over Hiroshima & Nagasaki who
survived the blast
 28% aborted
 25% gave birth to children who did not survive
their first year
 25% of the surviving children had abnormalities of
CNS
 e.g. Microcephaly & mental retardation

44. Prevention of birth defects
 Good prenatal care
 Iodine supplementation eliminates mental
retardation & bone deformities
 Prevent cretinism
 Folate/Folic Acid supplementation
 ⇓ incidence of neural tube defects
 Avoidance of alcohol & other drugs during all
stages of pregnancy
 ⇓ incidence of birth defects

45. Principles of teratology
 Were first formulated by Wilson (1959)
 Susceptibility to teratogens depend on genotype
and its environmental interaction
 Susceptibility varies with developmental stage at
time of exposure
 Most sensitive period for inducing birth defect is weeks 3-
8 of gestation
 Manifestations of abnormal development depend
on dose & duration of exposure
 Teratogens act in specific ways on developing cells
& tissues to initiate abnormal embryogenesis
 manifestations of abnormal development ⇒ death,
malformation, growth retardation, functional
disorders