Post on 15-Jan-2017
transcript
DRUGS IN PREGNANCY
During embryogenesis-drugs &chemicals may adversely affect development
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
Critical Periods
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%
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
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
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)
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
U.S.A. Temporal Trends for U.S.A. Temporal Trends for Limb Reduction Deformities, Bendectin Sales, Limb Reduction Deformities, Bendectin Sales, and Hospitalizations for NVPand Hospitalizations for NVP
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
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 insulinUndetectable umbilical cord levels with therapeutic maternal levels(50-150ng/ml)
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)
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)
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
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
Aminopterin Antagonist of Folic Acid Antineoplastic agent which inhibits mitosis Defects
Anencephaly Meningocele Hydrocephalus Cleft lip & palate
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
Trimethadione (syndrome) Malformed ears Cleft palate Cardiac defects Urogenital anomalies Skeletal anomalies
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
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
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
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
Recreational drugs PCP angel dust
Possible malformations & behavioral disturbances
Cocaine-vasoconstrictor hypoxia Spontaneous abortion Growth retardation Microcephaly Behavioral problems Urogenital anomalies gastroschisis
X
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
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
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 suspectedX
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 teratogenicX
Phenylketonuria (PKU) Enzyme phenylalanine hydroxylase is
deficient phenylalanine (PA) concentrations Mental retardation Microcephaly
Risk can be with low PA diet
X
Hypoxia Associated with congenital
malformations in a great variety of experimental animals In humans ???
Maybe smaller babies e.g. offspring at high altitude
X
Environmental Chemicals Mercury
Fish, seed corn sprayed with mercury containing fungicide Multiple neurological symptoms
Lead abortions Growth retardation Neurological disorders
X
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
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
XX
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
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
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
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 weeksX
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
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
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
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
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
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