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