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Prescribing drugs duringpregnancy and Teratology

COLLEGE OF MEDICINEDEPT. OF OBSTETRICS AND GYNECOLOGY

Prof.Ayman Hussien ShaamashMBBCH, MSc., MD. (Egypt)

Professor of OB./Gyn.Faculty of Medicine.

King khalid University

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1. General Considerations2. Inadvertent Exposure during pregnancy3. Definitions: Teratogens and Teratology4. Developmental stage and exposure to teratogens5. FDA fetal risk category6. Recommendations For prescription during pregnancy7. Other teratogenic conditions

Contents:

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√ Most drugs will diffuse passively across placenta,and some are transported actively, so the potentialbenefits to mother has to be considered in relationto the potential risk to the fetus

√ The safety of most drugs in pregnancy has notbeen firmly established as the effects may not beapparent for many years after birth.

√ The classic example is past use of stilboesterol inwomen with threatened abortion has resulted inDES syndrome up to 20 years later on

General ConsiderationsGeneral Considerations.

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In 1991 WHO International Survey ofDrug Utilization in Pregnancy stated that:

√ Nearly, Maternal and embryo-fetal effects ofmost medications are unknown for morethan 50% of medications

√ Up to 40-90% of women are exposed to oneor more drug medications during pregnancy

√ Despite this high rate of medication intake,most drugs are not labeled for use duringpregnancy

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Inadvertent Exposure

1/2 of pregnancies are unplanned ± 50% of women know they are pregnant by

4th week and ~20% still don’t know by 8th wk Teratogenic potential should be considered

and explained to women of childbearingage at time drug is prescribed

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As a general rule, all drugs shouldbe avoided in pregnancy unlessthere’s a compelling reason for

their use. Some drugs have beendefinitely linked to fetal major

abnormalities.

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Teratogens and Teratology:

Teratogen : Greek word teratos ( monster)are any agent that acts during embroynic orfetal development to produce a permanentalteration of form or function

Teratology is the study of abnormal fetaldevelopment

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Developmental stage and exposureto teratogens

Resistant period. day 0 to 11 postovulation, the fetus exhibits theall or none phenomenon ; that is, it will either be killed by the

insult or survive unaffectedMaximum susceptibility (embryonic period): days 11 to 57 of

gestation, the fetus is undergoing organogenesis and is mostsusceptible to the adverse effects of teratogens

Lowered susceptibility (fetal period): After 57 days (8 weeks) ofgestation, the organs have formed and are increasing in size.A teratogen at this stage may cause Growth retardation,hypoplasia of organ size or Functional derangements.

Susceptibility of the conceptus to teratogenic agentsdepends on the developmental stage at time of exposure.

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Structural or developmental defects

I. Malformations are morphologic defects of an organ or opart of the body resulting from an abnormality in thedevelopment in the first trimester.

II. Deformations are abnormal forms, shapes, or positionsof a body part caused by constraint within the uterus,usually occurring in the 2nd. or 3rd. trimester. i.e. clubfeetfrom oligohydramnios.

III. Disruptions are defects from interference with anormally developing organ system, usually occurring laterduring 2nd. or 3rd. trimester,i.e. amniotic band syndrome.

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USA-FDA fetal risk category

Category AFetal risk not revealed in controlled studies in humans

Category BFetal risk not confirmed in humans but has been shown insome studies in animals

Category CFetal risk revealed in animals but not established or notstudied in humans; use if benefits outweigh risk to fetus

Category DFetal risk shown in humans; use only if benefits outweighrisk to fetus

Category XContraindicated; benefit does not outweigh risk

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Teratogenic AgentsA- Ionizing radiation:

The dose of radiation and the gestational age during exposure arepredictive of the adverse neonatal effects

1-Acute high dose (more than 250 rad). At 2 to 4 weeks, either the fetus is normal or a

spontaneous abortion occurs. At 4 to 12 weeks, microcephaly, mental retardation,

cataracts, growth retardation, or microphthalmia . At 12 to 16 weeks, mental retardation or growth

retardation occurs. After 20 weeks, the effects are the same as with postnatal

exposure and include hair loss, skin lesions, and bonemarrow suppression

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1- After exposure to less than 5 rad to10 rad, an adversefetal outcome is unlikely to result.2- After exposure to 10 to 25 rad, some adverse fetaleffects may result.3- After exposure to> 25 rad, All classic fetal effectsoccurs, [ elective abortion should be offered as an option]

3- Radioactive Iodine: Radiation exposure equal to that ofradiographic procedures; with all adverse effects ofradiation,> the 10th wk of gestation, fetal thyroid destruction.

2- Low dose ionizing irradiation

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Average radiation dose of commonradiographic procedures.

The sievert (Sv) is the unit for equivalent dose in the System International(SI) nomenclature. For acute deterministic effects, large doses areusually required, such as 1-2 Sv

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B- Drugs and medications

The prohibition of all medications during pregnancyis impossible and may be more harmful to thepatient. However, the issue if a medication isharmful to the fetus is raised in most pregnancies.

Animal research can help identify teratogenicpotential, but results may be misleading because ofspecies variation. [e.g thalidomide]

Human controlled studies, Case reports and postmarketing long-term studies play a role in theidentification of teratogens.

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Major Known Human Teratogens

Alcohol (Ethanol) Carbamazepine Cytotoxic drugs DES Warfarin Isotretinoin Lithium

Methimazole Misoprostol Phenytoin Thalidomide Trimethoprim Valproic Acid Ionizing radiation

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Drug Safety During Pregnancy

• Safest: ampicillin, cephalosporins• Erythromycin: matemalliver damage (acute fatty liver) ,• Tetracyclines: stain children's teeth• Sulpha drugs: anti-folate properties, ? theoretical riskin T1 , risk of kernicterus in T3• Metronidazole: anti-metabolite, ? theoretical risk in T1• Chloramphenicol: grey baby syndromeFluoroquinolones: risk of cartilage damage .

ANTIBIOTICS

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Drug Safety During Pregnancy

OTHER MEDICATIONS

•ACE inhibitors: fetal renal defects, IUCR, oligohydramnios• anticonvulsants:

Phenytoin →fetal hydantoin syndrome in 5-10%Valproate & carbamazepine →NTD in 1%

•DES (other estrogenic or androgenic compounds): vaginaladenosis,adenocarcinoma, uterine malformation in daughters• Lithium: Ebstein's cardiac anomaly, goitre,hyponatremia

• Misoprostol:Mobius syndrome (facial paralysis ± limb defects)• Retinoids: CNS, craniofacial, cardiovascular, thymic anomalies

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Drug Safety During Pregnancy

OTHER MEDICATIONS

• Coumadin→ abortion, stillbirth, prematurity, IUGR• Fetal warfarin syndrome (nasal hypoplasia, epiphysealstippling, optic atrophy, MR, IVH)• Alcohol: →abortion and stillbirth, congenital anomaliesfetal alcohol syndrome (GR, CNS and facial anomalies)• Cigarette smoke: →IUGR, placenta previa/abruption,abortion, PTD, stillbirth• Cocaine: microcephaly, GR, prematurity, MR

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Other Possible Drugs Adverse Effects:

Spontaneous abortion

Intrauterine fetal death

Direct drug toxicity

Neonatal drug withdrawal

Long term effects[ neurobehavioral]

Carcinogenesis

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Inadvertent exposure to medication

Obtain accurate details of exposure , especiallygestational age , dose and duration of useCheck for confounding family and medical historyGet up to date information about the drugEmphasize the background riskBe clear about what is known , but do not

assume absence of data means no risk

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General Recommendations Forprescription during pregnancy

Tray and avoid 1st trimester

Minimize use of medications to those which are

necessary and for shortest duration possible

Effective drugs that have been in use for long

periods preferable to newer generations

Absence of data does not imply safety

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Other teratogenic conditions:

C. Hyperthermia ?? sustained maternal hyperthermia , not spiking,>101°F

[C°آ38.9] >24 hours between 4 and 14 weeks' gestation),is teratogenic.

Malformations noted include the following:1. Growth restriction2. CNS defects, as MR, microcephaly, hypotonia,

anencephaly, and risk of neural tube defects3. Facial anomalies :midfacial hypoplasia, cleft lip and palate,

microphthalmia, micro-gnathia, and ear anomalies4. Minor limb anomalies, such as syndactyly

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D. Maternal medical disorders

I.D.Diabetes mellitus. up to a 22% incidence of cardiac,renal, gastrointestinal, CNS, and skeletal malformations.Most of the malformations

Hypothyroidism. a twofold increase in stillbirths andcongenital anomalies. Cretinism is the result of maternal,fetal, and neonatal thyroid hormone deficiency

Epilepsy. is anexample of the contribution of a diseaseprocess and its treatment to an increase in birth defects.

Phenylketonuria: MR, Microcephaly, CHD ,LBW

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E. Maternal Perinatal Infections

Rubella virus (German measles). Cytomegalovirus (CMV). Herpes simplex virus type 2 (HSV-2). Toxoplasmosis. Syphilis.

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Phocomelia

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Warfarin Embryopathy

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Hydantion Embryopathy

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Valporate Embryopathy

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Fetal Alcohol Syndrome

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Congenital Rubella Syndrome

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