DRUG USE IN PREGNANCY AND LACTATION Drug use during pregnancy and lactation requires special consideration because both the

mother and the child are affected. Many pregnant or lactating women take drugs for acute or chronic disorders or habitual

use of alcohol and tobacco Pregnant women pose a set of therapeutic problems that must be considered before

prescribing medication She can exhibit altered pharmacokinetic and pharmacodynamics response to a number of

drugs She is subject to diseases unique in pregnancy e.g eclampsia Drugs are used in over half of all pregnancies and prevalence of use is increasing The most commonly used drugs include anti-emetics, antacids, antihistamines, analgesics,

antimicrobials, diuretics, hypnotics, tranquilizers, and social and illicit drugs. Over 90 % of expectant mothers take 3 or 4 drugs at some stage of pregnancy. Indications range from chronic illness such as epilepsy and depression to those commonly

associated with pregnancy such as hypertension, UTI and GIT complications All drugs administered to pregnant women have the potential to cross placenta and effects

on fetus Many drugs have potential for teratogenicity during 1st trimester During the first trimester, an older safe drug is preferred over a newer drug of unknown

teratogenicity. Live virus vaccines (measles, mumps, polio, rubella) should be avoided because of possible

harmful effects to the fetus. Inactive virus vaccines (influenza, rabies, hepatitis B) and toxoids (diphtheria, tetanus) are

considered safe for use. Human gestation period is approx. 40 weeks. Divided into 1st 2nd and 3rd trimester each lasting 3 months Another classification is according to stage of fetal development

1) Pre – embryonic stage: first 17 days post conception and involves implantation of fertilized ovum

2) Embryonic stage: days 18-56 major organ systems are formed 3) Fetal stage: days 8-38 involves maturation, development and growth

Placental transfer of drugs: Most drugs diffuse easily across placenta and thus enter the fetal circulation to some extent Some drugs are administered to treat fetal disorders e.g. flecainide to resolve fetal

tachycardia Drugs with large molecular weight like insulin and heparin have negligible transfer Drugs that are small, uncharged at physiological pH and highly lipid soluble cross placenta

rapidly e.g thiopental Charged drugs that are highly ionized at physiological pH diffuse across placenta more

slowly e.g. heparin and succinylcholine Some enzymes and transporters in placenta may facilitate or restrict the drug transfer Molecular weight of drug and extent of maternal plasma protein binding will also influence

the extent of diffusion Considerations in pregnancy:

Two major considerations: 1. Effect of drug on the pregnancy, fetus or neonate (teratogenicity and pharmacological

effects) 2. Effect of pregnancy on drug handling (Pharmacokinetics)

Altered pharmacokinetic and pharmacodynamics: During pregnancy mothers cardiac output increases up to 40 % Renal blood flow, GFR, and plasma volume increases Plasma albumin decreases All these result in altered pharmacokinetic and pharmacodynamics 50% Increase in plasma volume and body water: Water soluble drugs are distributed and “diluted” more than in the non-pregnant state Drug dosage requirements may increase Increased weight (~14 Kg) and body fat: Fat-soluble drugs are distributed more widely. Drugs distributed to fatty tissues tend to linger in the body because they are slowly released

from storage sites

Decreased serum albumin: The rate of albumin production is increased. However, serum levels fall because of plasma volume expansion

Many plasma protein-binding sites are occupied by hormones that increase during pregnancy

More free drug is available for therapeutic or adverse effects on the mother and for placental transfer to the fetus.

Increased renal blood flow and glomerular filtration rate secondary to increased cardiac output.

Increased excretion of drugs by the kidneys, especially those excreted primarily unchanged in the urine (digoxin, lithium)

In late pregnancy, the increased size of the uterus decreases renal blood flow in supine position

This results in decreased excretion and prolonged effects of renally excreted drugs. Pregnancy is hyper dynamic state, drug clearance may be increased (by renal

elimination/liver met) so maintenance doses of drugs often need to be raised Vd may be increased by 20 % for both lipid and water soluble drugs so increase in loading

dose may be required Measured drug concentration of highly PB drugs may be lower e.g. phenytoin

Normal physiological changes: Maternal plasma volume, cardiac output, and glomerular filtration increase by 30% to 50%

as body fat increases during pregnancy Nausea and vomiting, as well as delayed gastric emptying, may alter the absorption of

drugs Pregnancy-induced increase in gastric pH may affect the absorption of weak acids and

bases. Higher levels of oestrogen and progesterone alter liver enzyme activity and increase the

elimination of some drugs but result in accumulation of others Effects of drugs on pregnancy:

Majority of drugs attain concentrations in fetus close to those of maternal plasma Exposure during 1st 16 weeks of pregnancy is associated with an increased incidence of

physical malformation Less obvious effects e.g. decreased neuronal function or intellectual development may

occur following exposure later in pregnancy

Able to disturb the growth and development of an embryo or foetus. Drugs are classified as class A, B, C, D and X

Teratogenic:

A drug's effect on the fetus is determined largely by fetal age at exposure, drug potency, and drug dosage. Fetal age affects the type of drug effect: 1. Before the 20th day after fertilization: Drugs given at this time typically have an all-or-

nothing effect, killing the embryo or not affecting it at all. Teratogenesis is unlikely during this stage

2. During organogenesis (between 20 and 56 days after fertilization): Teratogenesis is most likely at this stage. Drugs reaching the embryo during this stage may result in spontaneous abortion, a sublethal gross anatomic defect (true teratogenic effect), or covert embryopathy (a permanent subtle metabolic or functional defect that may manifest later in life), or the drugs may have no measurable effect.

3. After organogenesis (in the 2nd and 3rd trimesters): Teratogenesis is unlikely, but drugs may alter growth and function of normally formed fetal organs and tissues. As placental metabolism increases, doses must be higher for fetal toxicity to occur.

Pharmacological risks: NSAIDS may cause premature closure of ductus arteriosus in later stage of pregnancy

Beta blockers can cause fetal bradycardias and hypoglycemia Ethanol and cocaine can cause teratogenic and toxic effects at birth as well as withdrawal

symptoms in neonates General principles:

Avoid all drugs if possible Avoid drugs in 1st trimester Choose drugs of proven safety or least toxicity Use short course and smallest doses

DRUGS DURING LACTATION

Breastfeeding mothers should avoid taking drugs if possible.When drug therapy is necessary, the mother should avoid contraindicated drugs and drugs that suppress lactation (bromocriptine levodopa)

When drug treatment is necessary, the safest known alternative should be used Drugs pass into milk by passive diffusion of free (unbound) and unionized form They are distributed within aqueous, protein and lipid phase of milk So drugs which are highly lipid soluble with low protein binding and unionized at

physiological pH achieve higher conc. in milk Nursing infants could ingest significant amount of drugs if it were present in breast milk in

higher conc. Nursing infants might be at high risk of toxicity as their renal, hepatic drug excretion is

immature, Sulphonamides, INH, Li, barbiturates, morphine, heroin, chloramphenicol, methotrexate cyclophosphamide should be avoided

Drugs Contraindicated for Breastfeeding Mothers: Dicumarol Warfarin Cytotoxic drugs (Cyclophosphamide, Methotrexate Diazepam, antipsychotics Corticosteroids