Drug in pregnancy

 Metabolism of drug in pregnancy

Pharmacokinetics & pharmacodynamics is quite different!

•       Intestines: enterocinesia↓        absorption ↑

•       Liver : Detoxifcation ↓

    Combining Power (with glucuronic acid) ↓

            drug accumulate in body

•       Kidney: GFR↑          drug cleen up↑

 But if kidney function impaired      retention ↑

 

 

    Influence of Drugs on fetuses

•       Indirectly :          

   by affecting the mother’s endocrine/ metabolism

•       Directly:

   pass the placental barrier to affect the fetus

 Teratology

Evaluation of Potential Teratogens

1.The Defect Must Be Completely Characterized

2.The Agent Must Cross the Placenta

3.Exposure Must Occur during a Critical Developmental Period

    preimplantation period-- the "all or none" period

    embryonic period-- structural malformations

    fetal period-- certain organs remain vulnerable

 

 Teratology

4.There Must Be a Biologically Plausible Association

5.Epidemiological Findings Must Be Consistent

6.The Suspected Teratogen Causes a Defect in an Animal

 Teratology

•         Evaluation of Potential Teratogens

 1. Careful delineation of clinical cases

 2. Rare environmental exposure associated with rare defect, with at least three reported cases—easiest if defect is severe

 3. Proof that agent acts on embryo or fetus, directly or indirectly

 4. Proven exposure to agent at critical time(s) in prenatal development

 5. Association must be biologically plausible

 

 Teratology

•       Evaluation of Potential Teratogens

 6. Consistent findings by two or more epidemiological studies of high quality:

    a. Control of confounding factors

    b. Sufficient numbers

    c. Exclusion of positive and negative bias factors

    d. Prospective studies, if possible

    e. Relative risk of three or more

 7. Teratogenicity in experimental, animals, especially primates

 

Classifications of Medicine by FDA  (Food and Drug Administration)

Category A—SAFEST, show no risk to fetus in the 1^st trimester and later in controlled studies in women.

    (Appropriate Vitamin)

Category B—Show no risk to fetus in animals, but there’s no controlled studies. Or show adverse effect in animal-reproduction studies which is not confirmed in controlled studies in women.

     (Penicillin, Erythromycin, Digoxin ,Insulin,ect)

Classifications of Medicine

Category C—Show adverse effect in animal-reproduction studies while no controlled studies in women. Or studies in animals and women are unavailable. These dugs should be given only when the potential benefits justifies the risk to the fetus.

   Gentamycin, Phenergan/Promethazine, INH(Isoniazid),ect

　

 

Classifications of Medicine

•         Category D—Positive evidence of human fetal risk exists. These drugs are available only when it’s needed in life-threatening situation, or for serious disease without safer effective drugs.

    Streptamycin Sulfate, tetracycline hydrochloride,ect

•         Category X—Dangerous!! Confirmed risks was shown in animals or human, or both. The risks of the use in pregnant women clearly outweighs any possible benefit.(Forbidden!!!)

　MTX(Methotrexate) Estrobene

 

Category C,D,X should be avoid in early pregnancy.

 

 

1.Disruption of Folic Acid Metabolism

     Folic acid –essential for the production of methionine

                      essential for normal meiosis and mitosis

     Methylation –PRODUCTION OF proteins, lipids,

                           and myelin.

 

Hydantoin, Carbamazepine,

Valproic acid, Phenobarbital

  

       Impair folate absorption or act as antagonists

 

2.Oxidative Intermediates

    a. In adults, oxidative intermediates normally are detoxified by cytoplasmic epoxide hydrolase.

    b. Fetal epoxide hydrolase is much weaker. Oxidative intermediates accumulate in fetal tissue.

    c. Free oxide radicals have carcinogenic, mutagenic, and other toxic effects

 

Hydantoin, Carbamazepine, Phenobarbital

 

3. Effects of Maternal Diseases

    The interaction of maternal disease and maternal and fetal genetic composition will determine some drug effects.

 

e.g. Alcoholic women with poor nutrition and abuse other drugs.

    fetus at higher risk of malformation

 

         Questions regarding medication and illicit drug use should be part of routine preconceptional and prenatal care.

                                                          -- ACOG, 1999

         Counseling should include possible fetal risks from drug exposure, as well as possible teratogenic risks or genetic implications of the condition for which the drug was prescribed.

 

         The manner in which information is presented affects the perception of risk.

Negative information—a 1 to 3 percent chance of having a malformed newborn— perceive an exaggerated risk.

Positive information—the 97 to 99 percent chance of having a normal child.

 

    Counseling should emphasize relative risk.

          All women have about a 3% chance of having a neonate with a birth defect, and although exposure to a confirmed teratogen may increase this risk, it is usually increased by only 1 or 2 percent, or at most doubled or tripled.

The concept of risk versus benefit also should be introduced. Some untreated diseases pose a more serious threat to both mother and fetus than any theoretical risks from medication exposure.

 

A. Alcohol

 

A. Alcohol

 

B. Anticonvulsant

Medications

 

 

C. Warfarin Compounds

     with a low molecular weight, cross the placenta,  cause significant adverse teratogenic and fetal effects.

 2 different developmental periods, 2 OUTCOMES.

 Exposed at 6^th ~ 9^th week, the fetus is at increased risk of warfarin embryopathy. This is characterized by nasal and midface hypoplasia and stippled vertebral and femoral epiphyses.

 

C. Warfarin Compounds

Warfarin embryopathy

        Inhibiting posttranslational carboxylation of coagulation proteins– osteocalcins-- embryonic control of calcification.

        Aberrant calcification of cartilage and premature calcification of bone happen.

        A phenocopy of chondrodysplasia punctata.

 

C. Warfarin Compounds

Warfarin embryopathy

 

C. Warfarin Compounds

Warfarin embryopathy

Dose dependent

Over 5 mg/day

72%-- Spontaneous abortion

8%-- Warfarin embryopathy

 

 

C. Warfarin Compounds

 During the 2^nd and 3^rd trimester

 Hemorrhage -- disharmonic growth and deformation from scarring several organs.

    a.Dorsal midline central nervous system dysplasia, such as agenesis of the corpus callosum, Dandy–Walker malformation.

    b.Midline cerebellar atrophy; ventral midline dysplasia such as microphthalmia, optic atrophy, and blindness; and developmental delay and mental retardation.

 

D. ACEI -- ACE inhibitor fetopathy

Papillary and tubular atrophy

       -- impairment in urinary concentrating ability

Prolonged fetal hypotension and hypoperfusion

       -- renal ischemia, renal tubular dysgenesis

       -- anuria, oligohydramnios

       --prevents normal lung development and causes limb contractures

       -- growth restriction, relative limb shortening, and maldevelopment of the calvarium

 E. Retinoids

a.Vitamin A-- Doses higher than the recommended daily allowance of 5000 IU（1000mcg） should be avoided.

b.Isotretinoin-- 13-cis-retinoic acid, is effective for treatment of cystic acne.

 Isotretinoin embryopathy-- Bilateral microtia or anotia with stenosis of external ear canal, Flat, depressed nasal bridge and ocular hypertelorism.

 E. Retinoids

Isotretinoin embryopathy

 F. Hormones

1.Androgens--autosomal recessive congenital adrenal hyperplasia and masculinization from exogenous.

a. Testosterone and Anabolic Steroids--Exposure of a female fetus results in varying degrees of virilization, including labioscrotal fusion after first-trimester exposure and phallic enlargement with later fetal exposure .

b. Androgenic Progestins--female fetus masculinization(1%).

 

F. Hormones

2.Estrogens

a. Diethylstilbestrol (DES)

        excess cervical eversion (ectropion) and ectopic vaginal glandular epithelium (adenosis-- malignant potential-- up to 50%

        abnormalities of the cervix or vagina—1/4

        a hypoplastic, T-shaped uterine cavity; cervical collars, hoods, septa, and coxcombs; and "withered" fallopian tubes

 

G. Antineoplastic Agents

a. Cyclophosphamide

--resulting in cell death and heritable DNA alterations in surviving cells.

--missing and hypoplastic digits on hands and feet.

--cleft palate, single coronary artery, imperforate anus, and fetal growth restriction with microcephaly.

 

 

G. Antineoplastic Agents

b. Methotrexate and Aminopterin

--alter normal folic acid metabolism.

--growth restriction, failure of calvarial ossification, anencephaly ， hydrocephalus ， cleft palat ，craniosynostosis, hypoplastic supraorbital ridges, small posteriorly rotated ears, micrognathia, and severe limb abnormalities.

 

H. Antimicrobials

a. Tetracyclines

--cause yellow-brown discoloration of deciduous teeth or be deposited in fetal long bones.

b. Aminoglycosides

--nephrotoxicity and ototoxicity have been reported in preterm newborns and adults. congenital defects resulting from prenatal exposure have not been confirmed.

 A. Anticoagulants

•              Warfarin Compounds

      AVOID!!（in　early　 pregnancy ）

•              heparin

•              Alteplase, tissue plasminogen activator (t-PA)

•              Streptokinase

•              low-molecular-weight heparins

 

ALL b,c,d and e are SAFE!!

 

B. Antimicrobials

•              Antibacterial Agents

      Penicillins are probably the safest.

      Cephalosporins, Erythromycin—SAFE!!

       Aztreonam—NOT teratogenic in ANIMALS.

       Chloramphenicol—POSSIBLE gray baby syndrome, manifested by cyanosis, vascular collapse, and death.

 

C. Psychotropic Drugs

b. Antidepressant Drugs

Selective serotonin reuptake inhibitors (SSRIs), a good choice for pregnant women.

Tricyclic antidepressants, no increase in the rate of fetal malformation was found.

Venlafaxine, FEW DATA.

Bupropion, FEW DATA.

Principal of drug usage in pregnant women

•        Using single medicine is safer than drug combination.

•        The medicine with certainly positive effect  is better than that with suspicious effect.

•        Small dosage is safer than large dosage.

•        Strict control the dosage and duration of administration is very important. Administration should be stopped timely.

 

Key points

•       In which period fetuses/embryos are the most sensitive to the drug adverse effect?

•       How dose the Food and Drug Administration(FDA) classify the drugs ?

•        What should we do in Counseling for Teratogen(drug) Exposure?

•       How to evaluate the effect of drug in fetuses/embryos?

 

 

 

 

[1]Which  could be the best choise for pregnant women with hypertension?

     A. ACEI                                  B. Nitroglycerin

     C. Sodium nitroprusside     D.CCB

[2]A woman needs cesarean section, which drug could be used in anesthesia?

     A. lidocaine                          B. procaine

     C. isoflurane                        D. all above   

 

[3]A pregnant woman with lower limb deep venous thromboses needs anticoagulant, which should be chosen?

     A. warferin                       B. heparin

     C. t-PA                              D. streptokinase

[4]Case discuss: A woman with mechanical valve comes to the prenatal clinic. She accepted warferin 2.5mg/d continuously since 3years before. What should you emphasize to her as a doctor on prenatal care?

 

[1] Williams Obstetrics 22^ND edition

                  The McGraw-Hill Companies, 2005

[2] Current Diagnosis & Treatment Obstetrics & Gynecology 10^th edition

                  The McGraw-Hill Companies, 2006