Drug Therapy in Pregnancy

Blok 17dr. H.Syahril Aziz, DAFK, Sp.FK., M.Kes.

Departement of Pharmacology

Medical Faculty

Sriwijaya University

I. Introduction.• The first principle of treating of pregnant woman with a

disease is to ask what would be a appropriate treatment in non pregnant state.

• There are several choices for pharmacologic management and for this reason the second principle is the evaluate and the relative safety of these choices of the patient and the fetus.

• In USA birth defect affect 2 – 3 % on neonates and cause 20 % of infant mortality.

• Exogenous causes of birth defect including radiation, infections, maternal metabolic disorder, chemical, traditional medicine affect 0,2 - 0,3 % of all births.

TERATOLOGY

• Derived from the Greek teras meaning MONSTER.

• Teratology is a study of abnormal development of the production of defects in the fetus.

U.S. Food and Drug Administration drug-risk categories.• Category A. Controlled studies in woman fail to demonstrated a risk to the fetus

in the first trimester ( and there is no evidence of a risk in later trimesters ) and possibility of fetal harm appears remote.

• Category B. Either animal reproduction studies have not demonstrated fetal risk

but no controlled studies in pregnant woman have been reported or animal reproduction studies have an adverse effect (other than a decrease in fertility ) that was not confirmed in controlled studies in woman in the first trimester ( and there are no evidence of risk in later trimesters).

• Category C. Either studies in animals have revealed adverse effect on the fetus

( teratogenic , embryocidal , or other) but no controlled studies in woman have been reported or studies in woman and animal are not available. Drugs should be given only if the potential benefit justifies the potential risk to the fetus.

• Category D. Positive evidence of human fetal risk exist, but the benefits

from use in pregnant woman maybe acceptable despite the risk (e.q. if the drugs in needed for a life threatening condition or for a serious disease for which safer drugs cannot be use or are ineffective).

• Category X.Studies in animal and human being have demonstrated fetal abnormalities, evidence exist of fetal risk based on human experience or both on the risk in pregnant woman clearly outweighs any possible benefit. The drugs in contraindicated in woman who are or may become pregnant.

II. Antibiotics and other antimicrobial agents in pregnancy and during lactation.

• Antibiotics are widely used during pregnancy.• Because of the potential of the maternal and fetal side effect

they should be used only when the indication is clear and risk : benefit ratio justifies their use.

1. Penicillins. have a wide margin of safety and lack toxicity for pregnant

woman and the fetus and drugs of choice in the treatment of bacterial infections. e.q. Amoxicillin.

2. Cephalosporins.The use of cephalosporin in obstetrics have been extensive. It used for prophylactic agents in cessarian section, septic abortion, pyelonephritis, amnionitis, but they have been well not studied in the first trimester.

3. Sulfonamides • The sulfonamide are often used for treatment of urinary tract

infection in pregnancy.

• No teratogenic effects were noted.

4. Nitrofurantoins.• is an antimicrobial agent used in tretment of acute

uncomplicated lower urinary tract infections as well as for long term supreesion in patient with chronic bacteriuria.

• No report linking the use of nitrofurantoin with congenital defects were found.

• The drugs is capable of inducing hemolytic anemia in patients deficient in glucose 6 phosphate dehydrogenase.

5. Tetracyclines.

• This drugs readily cross the placenta and are firmly bound by chelating to calcium in developing bone and tooth structure. This produce brown discoloration of the teet, hypoplasia of the enamel, inhibition of bone growth and other scletal abnormalities.

• Hepatotoxic has been reported in pregnant woman.• Relative Contraindication in pregnant woman and

lactation.

6. Aminoglycosides.• Its commonly used with penicillin and clindamycin in

treatment of post partum endometritis, septic abortion or endometritis.

• Its should be given during pregnancy only with serious gram negative infection are suspected.

• Streptomycin and Kanamycin has been associated with congenital deaffness, ototoxicity and nephrotoxicity.

7. Erythromycin.

• It is the alternate drug of choice to penicillin for many diseases in pregnancy and is use for primary treatment for mycoplasma and chlamydae.

• No teratogenic risk of erythromycin has been reported.

8. Clindamycin • It should be used in pregnancy only when anaerobic

infections are suspected that are not sensitive to other antibiotic.

• No teratogenic risk of clindamycin has been reported.

9. Metronidazole• Controversy regarding the use of metonidazole during

pregnancy was initiated when the drugs was shown to be positive in the Ames test, which correlated with carcinogenicity in animal.

• No risk birth defect could be determinated. • Drug of choice for trichomonacidal and amoebicidal activity.

10. Quinolones. • It have a high affinity for bone tissue and cartilage and may

cause arthrophaties in children. • No malformation and musculoscletal problem in ifant expose

in fisrt trimester. • It should be used in pregnancy only when anaerobic infections

are suspected that are not sensitive to other antibiotic. • No teratogenic risk of quinolones has been reported.

11. Acyclovir• No risk birth defect could be determinated.• No teratogenic risk of acyclovir has been reported.

12. Antituberculosis drugs.• There are no evidence of any teratogenic effect of isoniazid,

paraminosalicylic acid, rifampycin or ethambutol.

III. Treatment of upper respiratory tract infection and asthma in pregnancy.

1. Sedating anti histamin.• No teratogenic risk of tripolidin and chlorpheny

ramin maleate has been reported. 2. Non sedating antihistamin.• No teratogenic risk of loratadin and cetirizin has

been reported. 3. Oral decongestans.• No teratogenic risk of pseudoephedrine and

phenylpropanolamine has been reported.

4. Topical nasal decongestants.

• Two common topical nasal decongestants oxymetazoline and phenylephrine are considered safe during pregnancy.

5. Topical nasal steroids.• Major birth defect has been reported in pregnant

woman who use topical Beclomethazon. • Used the other topical nasal steroid dexamethasone,

flunisolide, fluticasone and triamcinolone have not been reported.

6. Beta symphatomimetics

• Short acting Beta symphatomimetics agents have been used treated asthma include terbutalin, albuterol, metaproterenol and pirbuterol.

• No teratogenic risk of Beta symphatomimetics has been reported.

• Serious side effect iclude pulmonary oedeem, myocardial ischemia, cardiac disrythmia, cerebral vasospasm, hypotension, hyperglycemia, decrease hemoglobin concentration, increase serum lactat level.

7. Theophylline

• It is a first line drugs in treatment of asthma. • No teratogenic risk of theophylline has been

reported. • Use of theophylline during lactation is not

contraindicated.

IV. Treatment of urinary tract infection in pregnancy

• Drugs that can be used as first line therapy of urinary tract infection in pregnancy include :1. Amoxicillin, ampicillin.2. Cephalosporin3. Erythromycin and azythromycin.4. Nitrofurantoin.

• Drugs that can be used as second line therapy of urinary tract infection in pregnancy include :1. Aminoglycoside2. Trimetophrim & sulfamethoxazole

V. Caffeine

• Caffeine (1,3,7 trimethyl xanthine) is an alkaloid present in several different plants.

• No teratogenic risk or birth defect of caffeine has been reported.

• Incidence of low birth weight and intrauterine growth retardation is controversial until now.

VI. Treatment of gastrointestinal disorder in pregnancy and lactation.

• Specific gastrointestinal disorders include :a. Nauseab. Vomitingc. Hyperemesis gravidarum

1. Pyridoxine ( Vitamin B 6 ).has been shown to reduce nausea and vomiting in pregnancy.

2. Dymenhydrinate (dramamine), Diphenhydramine,

hydroxizine, promethazine : has been shown to reduce nausea and vomiting in pregnancy.

3. Metocloperamide and Ondansetron : has been shown and the best to reduce nausea and vomiting in pregnanc

• No teratogenic risk or birth defect of the drugs has been reported.

VII. Anti hypertensive drugs in pregnancy

Hypertensive disorder in pregnancy is a major cause of maternal morbidity and mortality from cerebro vascular accident, uteroplacental insufficiency, abruptio placenta and prematurity.

1. Methyldopa.o It is drug of choice in pregnancy anti hypertension.o Onset 48 hours.o The maximum dose 2 go Side effect : hemolytic anemia, liver damage.

2. Beta Blockers.• No teratogenic risk or birth defect of Beta Blockers has been

reported. • Side effect : hypoxic fetus, fetal growth retriction,

hypoglycemia, bradycardia and hypotension.

3. Calcium Channel antagonists.• Antihypertensive effect throught both vasodilation and

negative inotropic action.• Only for severe hypertension in pregnancy because has a

rapid onset action. • Side effect : Hypotension.• No teratogenic risk or birth defect of Calcium Channel

Blockers has been reported

4. Hydralazine

• is an antihypertensive agent that achieved its effect through peripheral vasodilation.

• Adverse effect : hypotensive, fetal distress, headache, tachycardia, systemik lupus type syndrome, tachyphylaxis have all been reported.

5. Clonidine • Is a effective central acting hypertensive agent. • Adverse effect : lethargy, dizziness, dry mouth.• No teratogenic risk or birth defect of clonidine has been

reported

6. Diuretic Furosemide and Hydrochlorothiazid.

• If we have the alternative safe therapies, do not recommend to use this drugs in pregnancy.

7. ACE Inhibitors ( Angiotension receptor blockers).• It have been associated with fetalhypocalvaria, renal failure,

oligo hydramnions, and fetal and neonatal death especially in second trimester.

Conclusion.• The antihypertensive agent as a group of

drugs are relatively safe in pregnancy and not teratogenic exception ACE Inhibitors.

• It was suggested that antihypertensive agent reduce uteroplacental blood flow, fetal hypotension, hypoxia and that the anomalies were secondary to these event.

VIII. Analgesic Use in Pregnancy • Analgesics are among the commonly used medications in

pregnancy.

1. Aspirin. - is a non steroid anti inflammatory agent that act by irreversible inhibition of the enzymes necessary for the synthesis of prostaglandin.

- Cause constriction of the fetal ductus arteriosus with resultant pulmonary hypertension.

- Avoid during pregnancy.- increase risk of gastroschiziswhen taken in the first

semester.

• Concern about accumulation in the infant have led to recommendation that aspirin be avoided during lactation.

2. Acetaminophen• Is widely used during pregnancy.• It can cross the placenta but is considered safe when

taken in the normally recommended dosage.• No teratogenic risk or birth defect of acetaminophen

has been reported.

IX. Multivitamin and mineral supplementation in pregnancy

1. Vitamin A.• Is a fat soluble vitamin found in many vegetable foods group. • US FDA for pregnancy is 2700 IU. • Routine supplementation with vitamin A during pregnancy is

not recommended.• If supplementation is used, it should not exceed 5000 IU dayli,

because of the increase risk birth defects.

2. Folic Acid.• Is one of the B vitamin and an important role

in nucleoprotein synthesis and in the production of red blood cells.

• Folic acid deficiency in pregnancy is associated with neural tube defects (NTDs) and other anomalies.

• Placental abruption, intra uterine growth restriction, prematur delivery.

• The recommended dayli 0,4 mg/day.

3. Iron.• The recommended dayli 100 mg/day.• Iron absorption is inhibited by sat formation

with phosphate, caffein and antacids. • Iron preparationscan cause gastrointestinal

side effect such as an epigastric discomfort, metallic taste, constipation.

4. Calcium• In some studies, calcium supplementation of 1

g per day is associated with a decrease incidence of gestational hypertension.

5. Magnesium• Magnesium is an essentiale mineral found in bread,

cereal, vegetable, meats.• Magnesium works with many enzyme systems to

regulate body temperature and protein sythetis.

6. Zinc• Low serum zinc levels have been associated adverse

pregnant such as a small for gestational age infant, and labor abnormalities.

• Whether routine supplementation with zinc 20-60 mg/day.

X. Anticonvulsants in pregnancy 1. Phenobarbital.• is one of most commonly used AEDs in barbiturate class of

medication. • It is used in treatment of partial and generalize tonic clonic

seizures and status epilepticus.• Fetal exposure to phenobarbital has been associated with:

* congenital heart defect* orofacial clefting* decrease intelectual and cognitive development

• Maternal phenobarbital use during pregnancy can result : * hemorragic disease in new born* neonatal withdrawal symptom consist of mostly of irritability

2. Carbamazepin.• It is use to treat all type of seizure disorderwith the exception

ptit mal epilepsy. • It is most commonly used in treatment of psychomotor and

grand mall epilepsy.• The pregnant woman who taking carbamazepine increase the

incidence congenital anomalies :* craniofacial defect.* fingernail hypoplasia* developmental delay* hemorrhagic disease of the new born.

3. Phenytoin• Is used for the treatment of partial tonic clonic seizure and

status epilepticus.• The toxic effect :

• Ataxia, nystagmus, nausea, ginggiva hyperplasia, depression, megaloblastic anemia, dysrythmia.• Midline heart defect, orofacial cleft, urogenital defect.• Fetal hydantoin syndrome : is a constellation of minor

anomalies including craniofacial abnormalities ( short nose, flat nasal bridge, wide lips, hypertelorism, ptosis, epicanthal fold, low set ears, and low hairline) and limb abnormalities ( distal digital hypoplasia, abscent nails, and altered palmar crease). • Decrease of fetal coagulation factor associated with

increase risk of hemorrhagic diseasebecause decrease factor II, VII, IX and X.

3. Valproic acid

• Is used to treat absence, and generalized tonic clonic seizure.• Side effect : dyspepsia, nausea, tremor, alopecia, peripheral

edema.• Infant : Spina bifida, liver damage.

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