[At the end of the lecture, the student should be able to:-]

1. Identify the source of drugs administered to the patients.

2. Discuss the various factors (such as gestational age) involved in the transfer of drugs to the fetus.

3. Distinguish between a “safe” drug and a teratogen.

4. Define teratogens, and recognize teratogenic drugs and agents and the significance of avoiding such agents in obstetrics.

5. Understand the classification of drugs and its application to commonly prescribed drugs.

6. Recognise the common indications for drug administration in Obstetrics.

7. Appreciate that unusual indications (drug addiction/smoking etc) are quite important in obstetrics.

8. Discuss the adverse effects of some special drugs on the mother and the fetus and the need for caution in the use of such drugs; apply such knowledge to new or unfamiliar drugs.

9. Understand the basis of drug prescription for the obstetric patient and the importance of accurate record keeping of all drugs administered to the obstetric patient.

10.Understand the need to apply appropriate caution ( on the basis of the effects of drugs in the fetus) in drug usage for the wide variety of indications in gynaecology.

1. Introduction

2. Case Illustration

3. Drugs in Obstetrics

i. Sources of drugs

ii. Metabolism of Drugs

III. Transfer of drugs to the fetus

• Maternal factors

• The placenta

• The fetus

iv. Effects of Drugs on the fetus • Type of Drug •Teratogens • Gestational age • Route of Administration

v. Classification of Drugs vi. Indication for Drug use in pregnancy vii. Specific illustrations of Drug usage

in pregnancy

4. Drugs in gynecology

4. Questions

INTRODUCTION:

Drugs indicated in all aspects of Medical practice

Route of AdministrationDosage Regimes Indications Already coveredModes of Action in PharmacologyDuration of Usage LecturesToxic effects

In this lecture, we shall discuss

* Various aspects of drugs in Obstetrics

* Indications for use with emphasis

on gestational age

* Toxic effects (if any) of such drugs on

the fetus and mother

* General indications for drugs in

gynaecology.

A 30 year old P2+3+2+2 presented in the antenatal clinic with 8 weeks amenorrhoea. She had a mild stroke after her last delivery and she was diagnosed as protein S deficiency and was on treatment with warfarin. Discuss the management of this case.

Essential points

1. Age - 30yrs

2. Gravida 7 para 5

3. Previous preterm deliveries

4. Protein S deficiency

5. Warfarin Therapy

DRUGS IN OBSTETRICS

Importance of Topic Maternal effects

* Benefits

* Side / Toxic effects

Effects of drugs on the fetus

Incidence * Varies world wide

5 - 35%

Sources of Drugs to patients

* Over the counter

* Patient to patient

* General practitioner / other professionals

* Specialists (Obst. / Gyn. / others )

TRANSFER OF DRUGS TO THE FETUS1. Drugs usually administered to the mother

primarily and then transferred to the fetus (Physiologically)

- MORE IMPORTANT / FREQUENT ROUTE OF DRUG TRANSFER TO THE FETUS.

2. Occasionally, drugs may be primarily administered to the fetus.

Transfer of drugs to the fetus depends on

* Type of drugs administered

* Dosage / Duration of usage / Route of Drug administration.

Factors affecting transfer:

Maternal Factors Physiological changes of pregnancy

- Blood volume affect

- Serum albumin variation drug

and drug binding concentration

The role of the placenta - Transfer of drugs across the placenta

by simple passive diffusion

- drug transfer dependent on molecular weight of drugs

Virtually all drugs low in molecular weight cross placenta easily

Few Drugs ( Insulin / Heparin ) high in molecular weight dont cross placenta

Physical properties of drugs - Lipid solubility

Gestational age ( easier drug transfer near term)

Placental state ( chronic diseases lower transfer of drugs)

Role of the Fetus

* Circulation of drugs through fetal circulation

to all parts of the fetus

* Tissue specific uptake of drugs by some fetal tissues - Teeth ( Tetracycline ) - Mullerian ducts / vagina (Diethylstilboestrol) - Thyroid gland ( Iodides, Propyl thiouracil)

* Fetal drug metabolism / elimination.

EFFECTS OF DRUGS ON THE FETUS TERATOGENICITY

Depend on1. Type of drug

2. Gestational age at intake of drug by mother

3. Duration of intake / route of administration /

dosage of drug administered

4. Status of mother / fetus.

Type of Drug.Most drugs “safe” in pregnancy.

Some drugs have adverse effects on the fetus:

- destruction of cells / abortion

- Various grades of fetal malformation

- intra-uterine growth retardation/restriction

- cerebral damage / neurological damage

- mental retardation

- death of the fetus

Such drugs with major destructive effects on the fetus are

known as TERATOGENS.Other agents to which the mother is exposed may also

cause damaging effects on the fetus

Such agents are also called teratogens.

They include infections / chemicals / radiation.

DRUGS AND OTHER AGENTS AS TERATOGENSTeratogens include

Infections - Rubella : Toxoplasmosis, CMV

Chemicals : Isotretinoin

Radiation - Radioiodine

Drugs Thalidomide (30th -70th Day of Pregnancy)

Tetracycline

Some other tetratogenic Drugs are:

Diethylstilboestrol ( DES ) Valproic acidAminopterinCyclophosphamide AndrogensPhenytoin LithiumMethotrexate IsotretinoinAlcoholDanazolCoumarinsACE InhibitorsACE = Angiotensin- converting enzyme

2. Gestational age at drug intake by mother

Ist Trimester - Maximum damage from drugs

a. Ovum period

fertilization to implantation

b. Embryonic period

2nd - 8th week

c. Fetal period

8th - 12th week

2nd and Third Trimesters

- Fetal period -13th week to term

Effects of Drugs.

* 1st 3 weeks - abortions etc.

* 3rd week - 10th week period of organogenesis- malformations

Later in pregnancy - various effects

e.g. Tetracycline discolouration of teeth Effect of drugs may be detected soon after

abortion or delivery or much later in life - e.g. adolescent effects of diethylstilboestrol.

3. Duration / Route of Administration / dosage of Drug Administered.

4. Status of mother / Fetus

IMPORTANCE OF ACCURATE RECORD KEEPING OF DRUG INTAKE IN PREGNANCY

To document effect of drugs on the mother & fetus.

Data required

* Type of Drug / Dosage

* Gestation of pregnancy at intake of drug

* Duration of Drug usage / route of Administration

* Indication for drug intake

* Side effects / toxic effects reported by the

mother

* effects of drug on outcome of pregnancy

* any abnormal effects noted in the fetus at abortion / birth / neonatal period

* Any abnormalities noted in the infant / adolescent / adult.

CLASSIFICATION OF DRUGS USED IN PREGNANCYDrugs classified into various groups in the light of possible adverse fetal effects as recommended by FDA.

Category Description.A. No fetal risk factors demonstrated from controlled

studies. Drugs proven safe for use during pregnancy. e.g. prenatal vitamins.

B. Fetal risk not demonstrated in animal or human studies. Many drugs commonly used fall into this category e.g. Penicillins.

Acetominophen (Adol, Paracetomol ) Insulin, *Chloroquine, Nystatin.

C. Fetal risk may be known: No adequate human studies nor animal studies. In some cases, animal studies may demonstrate adverse fetal effects but no human data available e.g. Furosemide, methyl dopa, Aspirin,

Chlorpromazine. Again many drugs commonly used fall in this category

D. Some evidence of fetal risk known in humans: It may however be quite necessary to use such drugs, the benefitsof such drugs may thus be viewed as outweighing the risks of the drugs. e.g. Diazepam, Aspirin, Pethidine, Progestins, Corticosteroids, Tetracyclines etc.

X. Proven fetal risks. In this group the proven risks of the drugs outweigh any benefits for the drugs e.g. Isoretinein, an acne medicine.

INDICATIONS FOR DRUGS IN PREGNANCY.

A. Most Common Indications: Cardiovascular disease - Hypertension / Cardiac

/ Infections.

(Antibiotics and anti-infective drugs) G.I.T. Disorders Nausea / Vomiting Reflux oesophagitis Diarrhoeas

Respiratory DisordersAnalgesias - Mild / Strong/ Short term / Long term

Anaemias.

Most drugs used for above conditions /disorders are generally safe Category A/B/C drugs

Cardiovascular drugs used in pregnancyDrugs Category#ACE Inhibitors (capoten) C/Dβ – Blockers (Tenormin, Propanolol C

*Labetalol)Calcium antagonists (Nifedipine)Coumarins DDigoxin CFurosemide (Lasix) CHeparin (Mini – Heparin) CHeparn (Low molecular weight H: clexane, B

fraxiparine)Methyl Dopa (Aldomet) CThiazides DQuinidine C

Other DrugsDiazepam D# Should not be used in pregnancy

Antimicrobial Agents commonly used in pregnancyAntimicrobial agent Category of Drugs(FDA)Aminoglycosides C/DCehalosporins BErythromycin BAzithromycin BChloroquine CImipenem CMetronidazole BNitrofurantion BPenicillins BSulphonamides BTetracyclines DTrimethoprim (Septrin/Bactrim) CVancomycin C

AntiviralsAcyclovir CGanciclovir BZindovudine C

AntiprotozoalsQuinine DMebendazole C

AntifungalsAmphotericin BFluconazole CIntraconazole CNystatin B

B. Other Indications CNS - Epilepsy

- Sedatives

- Psychiatric

Haematological - Oral anti-coagulants

Hormone therapy -

Malignancies -

Many drugs used for above indications are

rather unsafe and fall into category D.

C. Unusual Indications - Drugs that cause addiction

HeroinCocaine DangerousAmphetamine with-drawal Methadone effects

Alcohol - Excessive intake definitely dangerous

D. Smoking

E. The Uterus Tocolytic Agents - Ritodrine

Stimulants - prostaglandins / syntocinon

Drugs used for above indications usually safe

F. Drugs and Lactation

Suppression of lactation

Most drugs excreted in small amounts in breast milk.

No major adverse effects on the fetus.

Indications for Drugs usage in the labour ward

Indications:

A. Hypertension - Acute Hypertension

Severe PIH/ Eclampsia

- Pulmonary Oedema

B. Acute Respiratry distress (Maternal)- Acute / severe Asthmatic Attack

- Mendelsohn’s Syndrome

- Severe Respiratory Infection

Prevention of Neonatal RDS

C. Induction of Labour- Augumentation of labour

D. Obstetric Haemorrhage- Intrapartum Postpartum

E. CNS Disorders- Epilepsy

F. Anaesthesia/Analgesia - Epidural / General

G. Others- Diabetes mellitus- Cardiac disease- Systemic Infections etc

DIC

Drugs Frequently prescribed:Labetalol Digoxin/Drugs for cardiac ArrythmiasHydrallazine Furosemide (Lasix)Magnesium sulphate Heparin (protamine sulphate)LasixDiazepamEpanutin (phenytain sodium)HydrocortisoneAminophyllineZantacDexamethasone / BethamethasoneProstaglandin E2

(Pessaries – 3mg; 1.5mg)* Postaglandin F2x*

Syntocinin Analgesic AgentsSyntometrine Entonox / Pethdine / Morphine/

(Nalorphine)Methergin Anaesthetic AgentsErgometrineRitodrine / Tocolytic AgentsAntibioticsPenicillinsCephalosporinsAminoglycosidesMetronidazoleInsulin InjectionsBlood products / Intravenous fluidsOthers – vitamin K injection

Route of administration- Intravenous- IntramuscularDosage of DrugsSide – Effects of Drugs- Complication / Anaphylaxis

SPECIAL CASES OF DRUG USE IN PREGNANCY AND THE EFFECTS ON THE FETUS

1. Anti- Coagulants a) Heparin - High molecular weight (12,000)

Doses not cross placenta to fetus Does not cause major fetal effects Maternal risks over prolonged usage

include - Osteoporosis - Thrombocytopaenia - Vaginal bleeding / placental abruption (May cause expected fetal risks - SB etc)

Heparin is the preferred anti-coagulant in pregnancyIndicationsRoute of administrationDosage Regime

LOW MOLECULAR WEIGHT HEPARINS

CURRENTLY USED HEPARIN* RECENTLY INTRODUCED

TO MATERNITY HOSPITAL

Mini-Heparin (Calcium Heparin) CLEXANE ENOXAPARIN (other brands exist)

Mol. Wt.: 12,000-15,000 Daltons Lower molecular weight Mol.Wt: 5000 Daltons

Does not cross the placenta does not cross the placenta

DOSE :- DOSE :-5,000 - 10,000 UNITS 20 mg - 40 mg

(pre - loaded syringe)

Subcut 12 hrly (or more Subcut (Anterior abdominalfrequently in some cases) wall)

* Unfractionated heparin DAILY

b) Oral Anti- Coagulants -Warfarin etc.Low molecular weightEasy transfer through placenta to fetus Major adverse effects on fetusWarfarin is the preferred oral anti-coagulant that should be

prescribed in pregnancy ( if indicated )BUT - It causes major adverse fetal effects.Ist trimester. ( Greatest risk 6-9 weeks gestational age )

“Fetal warfarin syndrome”- Nasal hypoplasia Deafness Stippled vertebra and femoral epiphyses- Spontaneous abortion / Fetal death- IUGR / Developmental Delay

In 2nd and 3rd Trimester, Warfarin usage also associated with multiple adverse effects.

- Optic atrophy

- Cataracts

- Mental retardation

- Microcephaly

- Hydrocephaly

- Blindness

- IUGR

Oral anti-coagulant best avoided in pregnancy (especially in the first trimester)

May be used in very special circumstances with caution

2. Anti-Convulsants: Transferred across placenta. Two - three fold risk of malformed fetus in mothers on anti-convulsants compared with controls Phenobarbitone - Small risk of fetal anomally exists Meprobamate - Risk of fetal defects.

Phenytoin ( Epanutin ) Folic acid antagonist Megaloblastic anaemia in the mother. Coagulation defects in the mother

Reports of fetal anomaly exist

“Fetal hydantoin syndrome”

Noted in some reports

- Craniofacial / limb malformations

(hypoplasia of distal phalanges)

- Mental retardation

- Growth retardation

Folic Acid supplementation recommended before onset of pregnancy ( where possible ) to reduce adverse effects.

Carbamazepine (Tegretol ) Fetal effects similar to those due to phenytoin

Valproic Acid-

Micro cephaly

Neural tube defects

Use should be avoided

Maternal side effects and

In Epilepsy , inspite of fetal hazards from the drugs used, medical therapy must be continued all through pregnancy in the interests of the mother.

3 a. Analgesics: Easily transferred across placenta to fetus Mild analgesia - Acetaminophen (Paracetamol - Adol) safe in pregnancy No fetal effects. Mild oral analgesic / antipyretic of choice in

pregnancy.

3 b.

Aspirin: Suggested fetal risk if used in first trimester.

- Prostaglandin synthetase inhibitor

Prolonged usage in 3rd trimester associated with

- Decrease in platelet adhesiveness and aggregation

- Increased incidence of neonatal bleeding, especially intracranial bleeding

Prolonged usage in standard or high dosage should be avoided. Could also cause GIT bleeding in mother .

3 c. Use in smaller doses (Baby aspirin for PIH and

Recurrent abortions due to Antiphospholipid syndrome ) not associated with fetal risks.

Ibuprofen - Non -steroidal anti-inflamatory (Brufen) analgesic Relatively new drug Risk similar to aspirin; use with caution

Indomethacin - Adverse fetal effects (Indocid )

Aspirin / Indomethacin / Non-steroidal anti inflamatory agents which inhibit prostaglandin synthesis may cause premature closure of the fetal ductus arteriosus with adverse fetal effects

These drugs in high dosage could arrest premature labour,prevent onset of labour, and prolong the pregnancy. Caution!

Stronger Analgesics: (In labour, etc) Pethidine Cause depression of respiratory Morphine system of neonate: Antidote is

Naloxene.

4. Sedatives Transferred across the placenta to the fetus

Diazepam: (Valium)

Small incidence of cleft lip / palate reported with first trimester usage .

In third trimester / labour: - Sedates the fetus

- Loss of beat to beat variation {NSTα CTG chart }

(depression of fetal medullary centre)

- Neonatal hypotonia, hypothermia / apnoeic attacks reported.

Monitor neonate carefully.

Use Diazepam with caution Other sedatives - Be Cautious !

DRUGS IN GYNAECOLOGYDrugs in gynaecology less complicated.No adverse fetal effects to contend with Indications for drugs in gynaecology same as in general Medical

Practice and surgical practiceSpecial Indications for drug usage in gynaecology - General Infections

- Hormone therapy - Infertility / Pelvic and Vaginal infections (Antibiotics,Antifungal

agents etc) - Contraception

- Oncology (chemotherapy)- Classification- Side effects

ALWAYS ASK ABOUT MENSTRUAL HISTORY ( L.M.P ) and thus EXCLUDE PREGNANCY BEFORE DRUG PRESCRIPTION IN GYNAE.

KEEP RECORDS OF DRUGS USED

QUESTIONS

Write shorts notes on :-

1. Magnesium sulphate

2. Methotrexate

3. Clexane

4. Bromocriptine

5. Methergin

6. Aspirin

7. Epanutin

Short Notes on Format for above Questions:-1. Type of drug

- Brief Notes

2. Indications for Drug

3. Dosage / Route / Mode of administration

4. Mode of action

5. Side Effects / Toxic Effects

6. Prevention of Side Effects / Toxic Effects