80

Drugs, Pregnancy and the Infant

Drugs are likely to be self administered or prescribed by the physician during
pregnancy. Intelligent use of drugs during pregnancy requires that the physician
understands the interaction between drugs and pregnancy so as to avoid indiscriminate
use of drugs with disastrous consequences as illustrated by the thalidomide tragedy. At the
same time, overcautious timidity on the part of the physician casts the pregnant mother in
the role of a therapeutic orphan. It must be remembered that most of the drugs prescribed
during pregnancy are given for the benefit of the mother and that one must not deny her
adequate treatment for a serious illness.
In addition to drugs, the pregnant woman is likely to be exposed to a variety of environmental,
non-therapeutic or illicit agents which can affect the fetal health.
Pharmacokinetics During Pregnancy
Most of the available information on pharmacokinetics of drugs during pregnancy has
been obtained from animal experiments and may not be directly applicable to humans.
Although pregnant women do not differ qualitatively from the non-pregnant ones in their
response to drugs, certain quantitative differences do occur because of physiological
changes during pregnancy, with consequent alterations in pharmacokinetics of drugs.
Further, the fetus has its own pharmacokinetic peculiarities.
Drug absorption: High circulating levels of progesterone slow the gastric emptying as
well as gut motility, thus increasing the intestinal transit time. As a result, one might
expect slower drug absorption during pregnancy. However, this does not occur except at term
when parenteral drug administration is preferred in order to obtain a quick response.
Administration of iron and antacids may also interfere with the absorption of certain
drugs. Drug compliance may be poor during pregnancy because of nausea and fear of
possible adverse effects.
Drug distribution: Pregnancy is accompanied by an increase in total body water by upto
8 litres and a 30% increase in plasma volume, with consequent decrease (0.5 - 1.0 g%) in
plasma albumin due to hemodilution. Drugs which have low lipid solubility and are also
highly plasma protein bound (e.g. warfarin, benzodiazepines) have a low apparent volume
of distribution (Vd). The Vd of such drugs increases markedly during pregnancy. The
protein bound fraction of the drug in the plasma diminishes and so does the concentration
of the total drug in the plasma. Although the fraction of unbound drug increases, a greater
pharmacodynamic effect is prevented by more rapid elimination of the drug by
metabolism and/or excretion (see below). The therapeutic range for drugs whose use is
monitored by measurement of total plasma concentration (e.g. phenytoin) must be
adjusted downwards to make allowance for the above mentioned changes, if their plasma
protein binding changes during pregnancy. There is also likely increase in body fat which
acts as a reservoir for lipid soluble drugs.
Drug metabolism: Hepatic drug metabolising enzymes are induced during pregnancy, probably
by the high concentrations of circulating progesterone. This can lead to more rapid metabolic
degradation, especially of the highly lipid soluble drugs such as phenytoin and
theophylline. However, this is of little clinical consequence because the metabolism of
most such drugs is ordinarily so fast that their clearance is limited only by hepatic blood
flow, which does not change appreciably during pregnancy e.g. pethidine. The contribution
of the placenta and the fetal liver to the clearance of drugs from the maternal body is
thought to be small.
Drug excretion: During pregnancy, the renal plasma flow increases by 100% and the GFR
by 70%. Add to this the increase in the unbound fraction of the drug in the plasma. Hence,
drugs which depend for their elimination mainly on the kidney are eliminated more
rapidly than in the non-pregnant state. Examples are ampicillin, aminoglycosides,
cephalexin and digoxin.
The conventional dose of ampicillin needs to be doubled during pregnancy if it is used for a
systemic infection in the mother, but not if it is used for a urinary tract infection. An increase in
the dose of cefuroxime and lithium is needed for similar reasons. In the case of phenytoin
(whose unbound plasma level diminishes due to more rapid metabolism, in addition to
total plasma level), an increase in the daily dose by 25-100 mg may be required to maintain
good seizure control; a similar increase is also required in the dose of phenobarbitone and
carbamazepine. In spite of pharmacokinetic alterations, the doses of benzodiazepines,
aspirin, propranolol, sulfafurazole and metronidazole do not require alterations during
pregnancy. The pharmacokinetics of furosemide do not alter during pregnancy and no
dose adjustment is required.
Drugs, the Fetus and the Newborn
Placental transfer of drugs: The placenta acts as an intravenous portal for entry of drugs
into the fetus. Such entry of drugs is governed by several considerations. As pregnancy
progresses and the placenta develops, the surface available for transfer between the
maternal and fetal circulations increases; at the same time, the placento-fetal barrier
becomes progressively thinner. Transfer across this barrier is governed by the same
properties of drugs which regulate the transfer across other biological membranes:
unbound, non-ionised, lipid-soluble molecules of low molecular weight cross the barrier more
easily than those which do not possess these attributes; most of the drugs in use fulfil these
criteria and are able to cross the placental barrier. However, because of the differences in
the plasma protein concentration and the pH between maternal and fetal blood, the
concentration of drugs in the two circulations, even at equilibrium, may differ
considerably. Add to this, the differences in pharamacokinetics between the mother and
the fetus. Further, the placenta is capable of metabolising drugs; this is of little relevance
to the mother but can protect the fetus from the entry of many drugs. For example,
prednisolone and hydrocortisone, which are metabolised by the placenta to inactive
compounds are safer for the fetus than dexamethasone and betamethasone, which are not
so metabolised.
The method of drug administration to the mother may also decide the fetal
concentration. For example, at term, antibiotics given by intermittent intravenous infusion
can achieve higher concentrations in the fetal blood and amniotic fluid than when the
same total dose is given by continuous infusion; this may be important in the treatment of
intrauterine infections.
In spite of above considerations, the fetal: maternal ratio of unbound drug concentration
is generally close to unity. Further, the placenta is always available to the fetus as a route of
drug elimination. After birth, the placental route of drug elimination is no longer available
and the neonate is on its own.
Compared to adults, both fetus and infants differ in their handling of drugs, as related
to pharmacokinetics as well as pharmacodynamics.
However, the data available regarding this is far from adequate.
Fetal/Neonatal pharmacokinetics: Human growth is not a linear phenomenon. Age-
related changes in body composition and organ function are dynamic and can be
discordant during the first decade of life. Hence, the simplified dosage approaches calculated by
standard formulae may not be adequate for individualising drug doses across the span of infancy
and childhood.
During the neonatal period, intragastric pH is relatively higher (>7.4). Hence, orally
administered drugs such as penicillin G have greater bioavailability in neonates than in
adults. On the other hand, weak acids such as phenobarbitone need higher doses in the
young children. Generally, the rate at which majority of drugs are absorbed is slower in the
neonates than in the older children. Further, developmental differences in the activity of
intestinal drug metabolising enzymes and changes in the intestinal microflora may also
affect the plasma levels of drugs.
Compared to adults, neonates and infants have relatively larger extracellular and total
body water spaces. This, along with the adipose tissue stores that have a higher lipid/water
ratio, leads to lower EC concentrations when drugs are given on weight basis. Distribution
of highly protein bound drugs is also modified by the amount of circulating plasma
albumin and alpha 1-acidglycoprotein.
In infants and young children, the ratio of total body surface area (BSA) to body mass far
exceeds that in adults. Hence, the relative systemic exposure of infants to topically applied drugs
such as glucocorticoids may exceed that in adults, leading to adverse systemic effects.
Delayed maturation of hepatic drug metabolising enzymes in infants can cause
increased drug toxicity e.g. chloramphenicol.
The expression of Phase I metabolising enzymes such as cytochrome P-450 undergoes
marked changes during development of neonates. This affects the hepatic clearance of
various drugs metabolised by the isoforms of these enzymes. The clearance of
carbamazepine is greater in children than in adults. In the case of phenytoin, its t½ is
about 75 hours in preterm infants, which decreases to about 20 hours during the first week
of life and to 8 hours after the second week of life. The plasma clearance of morphine is
known to quadruple between 27th and 40th weeks of gestational age, thus requiring
corresponding increase in the dose of morphine for effective analgesia.
Because of significant developmental changes during the neonatal period, drugs such as
methylxanthines, morphine, captopril and third generation cephalosporins need age-
appropriate dosage regimens.
Various developmental changes in the kidney function during infancy can alter the
plasma clearance of drugs that are primarily excreted by the kidney, e.g. aminoglycosides,
famotidine, ceftazidime, digoxin, chlorpropamide, penicillin, salicylic acid, indomethacin
and paracetamol. This obviously will need age-appropriate selection of dosage regimen.
In view of the above problems, it is safer to consult worked-out dosage tables for neonates and
infants than to use formulae based on body weight and/or BSA.
Fetal-neonatal pharmacodynamics: Age-dependent differences in the interaction of the
drugs with specific receptors does probably exist but the data are limited. This may modify
the safety and efficacy of drugs in the neonates and infants. For a given plasma
concentration, the response of the fetal tissues to most drugs is equal to or less than that of
maternal tissues. There are some notable exceptions. Certain drugs given in the second
and third trimesters produce either exaggerated effects or effects that are unique to the
fetus. For example, tetracyclines get deposited in the fetal teeth and bones and retard their
growth; coumarins can cause fetal and neonatal hemorrhages. Salicylates given at term can
cause neonatal hemorrhage. PG synthetase inhibitors (NSAIDs) given near term can
induce premature closure of ductus arteriosus and pulmonary hypertension in the fetus.
Antithyroid drugs can inhibit fetal thyroxine synthesis and can cause goitre formation.
Opiates and barbiturates (given to mother) achieve very high concentrations in the fetal
brain and can cause respiratory depression at birth. Phenothiazines given to the mother
can cause extrapyramidal toxicity in the neonate which may persist for several months.
(Also see Chapter 13).
Effects of Drugs on Pregnancy
Effective treatment of maternal illness with drugs such as insulin, thyroxine, antibiotics
and antihypertensives may be said to have a beneficial effect on the course of pregnancy.
On the other hand, in certain situations drugs can cause harm to the conceptus. These
harmful effects depend upon the nature of the drug and its dose and route of
administration; the stage of pregnancy at which the drug is used; and the genetic
constitution and susceptibility of the fetus, which in turn, depend upon the age,
nutritional status and health of the mother. Gestation may be divided into four major
stages.
• Pre-implantation stage (blastocyst formation) which lasts about 16 days from conception
to implantation. Exposure to harmful drugs (such as anticancer drugs) can kill the
embryo or else the damaged cells are replaced by undifferentiated cells which have the
potential to develop normally. This is an all-or-none effect.
• Period of organogenesis from 17th to 56th day. Pre-implantation stage and the stage of
organogenesis together constitute the first trimester. Exposure to harmful drugs (and
other environmental influences) during the period of organogenesis can cause
congenital malformations (teratogenicity) or abortion.
• The second and third trimesters are periods during which considerable growth and
development occur in teeth, bones and in central nervous, endocrine, genital and
immune systems. During this period drugs can cause either teratogenesis or a variety of
other effects such as retardation of physical or brain growth, behavioural teratogenicity,
premature labour, neonatal toxicity and even late post natal effects such as cancer(s).
• A short labour-delivery stage: Drug administration during this period is mainly fraught
with the danger of toxicity in the neonatal period for reasons already discussed.
Teratogenicity
This word was originally used in the sense of congenital malformations grossly visible at
birth and caused by exposure to exogenous agents (teratogens) in the first trimester. The
definition has now been broadened to include any birth defect (morphological,
biochemical or behavioural) induced at any stage of pregnancy and detected at birth or
later in life. Birth defects are known to occur in 2-4% of all births in the population. Out of all
birth defects, the cause is unknown in 65-70%; 25% can be attributed to genetic defects and
3% to chromosomal aberrations. Only about 3% can be ascribed to environmental factors
including maternal infection, radiation and drug administration. The overall incidence of
congenital malformations does not appear to have increased in the last 30 years in spite of
the dramatic increase in the number of drugs available.
Teratogenesis includes restricted growth of the fetus, malformations, carcinogenesis and
behavioural teratogenicity (see later). It should be noted that fewer than 30 drugs have
been proved to be teratogenic in humans when used in clinically effective doses. Many of
the commonly used drugs, once thought to be teratogenic, have been shown by
subsequent studies to be safe; they include salicylates, glucocorticoids, diazepam,
combination OC pills and spermicides. Much of the information on teratogenicity of drugs
has been obtained from animal experiments and mishaps in clinical practice. Because of
species variability and the high doses used in these experiments, such data are not directly
applicable to humans; but they have a high positive predictive value. Almost every drug
that has been found to be teratogenic in humans has caused similar teratogenicity in
animals. However, there are drugs that have caused teratogenic effects in animals in large
doses that are not teratogenic in humans in clinically effective doses. Individual case
reports and limited epidemiological surveys provide the information available about
teratogenicity of drugs in humans.
Except in a few instances, congenital malformations produced by drugs are not unique.
In animal experiments, a given drug may produce different congenital abnormalities
whereas a given congenital abnormality may be produced by several drugs. Most drugs
currently suspected of being teratogenic in humans are, in fact, weak teratogens and
probably increase the frequency of congenital malformations only 2-3 fold. In fact, smoking
and alcohol are more harmful to the fetus than most drugs. Table 80.1 lists the drugs which are
known or suspected to be teratogenic in humans. Absence of a drug from the list should not be
interpreted to mean that it is necessarily safe during pregnancy.
Table 80.1
Drug with proven teratogenic effects in humans

Drug Teratogenic effect

Methotrexate CNS and limb malformations
ACE inhibitors Prolonged renal failure in the neonate, renal tubular dysgenesis, dec reased skull ossific ation.
Anticholinergic drugs Neonatal mec onium ileus
Antithyroid drugs Fetal and neonatal goitre and hypothyroidism, aplasia c utis (with methimazole)
Carbamazepine Neural tube defec ts
Cyclophosphamide CNS malformations, sec ondary c anc er
Danazol and other androgenic drugs Masc ulinisation of female fetus
Diethylstilbestrol Vaginal c arc inoma and other genitourinary defec ts in female and male offspring
Lithium Ebstein’s anomaly
Misoprostol Moebius syndrome
NSAID Constric tion of the duc tus arteriosus, nec rotising enteroc olitis
Oral hypoglycemic drugs Neonatal hypoglyc emia
P henytoin Growth retardation, CNS defec ts
P sychoactive drugs Neonatal withdrawl syndrome when drug is taken in late pregnanc y
Systemic retinoids (isotretinoin, etretinate) CNS , c raniofac ial, c ardiovasc ular and other defec ts
Tetracycline Anomalies of teeth and bones
Thalidomide Limb-shortening, internal organ defec ts
Trimethadone Malformed ears, c left palate, c ardiac , urogenital and skeletal defec ts
Valproic acid Neural tube defec ts
Warfarin S keletal and CNS defec ts, Dandy-Walker syndrome

FDA ratings for drug use in pregnancy are shown in Table 80.2.

Table 80.2
Drugs used in pregnancy, US FDA categories

FDA Rating Conditions Examples

A Controlled human studies show no risk Folic ac id
B No c onfirmatory evidenc e of risk in humans Metronidazole
C Risk c annot be ruled out Most drugs
D Positive evidenc e of risk exists Antiepileptic s (Table 80.1)
X Absolutely c ontraindc ated Cytotoxic s, Etretinate (Table 80.1)

The teratogenic effects of thalidomide have been described in Chapter 1; those of

alcohol in Chapter 6; tetracycline in Chapter 49 and retinoic acid derivatives in Chapter 71.
Patient is advised to delay pregnancy for certain periods of time after completing the
course of certain drugs: one month after isotretinoin (Chapter 71); three months after
mefloquine (Chapter 56); one year after cytotoxic drugs (methotrexate, cyclophosphamide);
and three years after etretinate (Chapter 71) in order to allow the elimination of the drug.
However, azathioprine following renal transplantation has not been found to pose an
excess risk of congenital malformations in succeeding pregnancies.
Testosterone and its derivatives, including progestogens derived from 19-
nortestosterone, can masculinise the external genitals of a female fetus. Estrogens and
progestins, on the other hand, are known to induce defective masculinisation of the
external genitals of a male fetus. However, inadvertent continuation of a COC pill during
the first month of gestation has not been found to be harmful to the fetus.
Diethylstilbestrol administration during pregnancy has been associated with the
development of congenital anomalies of external genitals in fetuses of both sexes, and with
the development of vaginal adenosis and vaginal adenocarcinoma in girls whose mothers
had received the drug.
The use of coumarin anticoagulants is associated with congenital malformations and
high incidence of fetal loss from abortion, retroplacental and intracerebral fetal bleeding.
Consumption of even one drink (10 g of alcohol) per day is associated with fetal growth
retardation and an increased incidence of abortion. Consumption of large quantities (40 g per
day) is associated with ‘fetal alcohol syndrome’.
Behavioural teratogenicity: Apart from the structural teratogenicity, drugs can also cause
behavioural teratogenicity i.e. abnormal behaviour in the newborn. Such effects have been
observed in animal models when drugs such as reserpine, phenothiazines, barbiturates,
amphetamine and cannabis were administered during pregnancy. So far, behavioural
teratogenicity has been observed in human newborns of mothers who were exposed to
methylmercury by eating contaminated fish and those who smoked during pregnancy.
Animal studies indicate that the developing CNS is highly susceptible to the effects of
psychoactive drugs. In humans, the brain development extends into early infancy and
hence, the extended vulnerability of the brain in humans to the effects of such drugs.
Table 80.3 lists points to remember while prescribing drugs to women who are of the
reproductive age and sexually active.

Table 80.3
Points to remember while prescribing drugs to a woman of reproductive age
Drug-Prescribing During Pregnancy
Table 80.4 summarises the precautions to be taken while prescribing drugs to a pregnant
woman.

Table 80.4
Precautions while prescribing drugs to a pregnant woman

Nausea and vomiting of pregnancy can be treated without drugs in most women.
Reassurance and high carbohydrate diet will help them. If required, an antihistaminic-
antiemetic (cyclizine, meclizine, diphenhydramine, dimenhydrinate) may be prescribed.
Metoclopramide is safe in the third trimester of pregnancy and may be prescribed in
resistant cases.
Heartburn is very common in pregnancy and is relieved by a small carbohydrate meal;
by avoiding fatty food, smoking and alcohol; and by maintenance of upright posture.
Consumption of aerated lemonade 2-3 times a day may also be helpful. Non-systemic
antacids and metoclopramide may be needed in some cases. Anticholinergics usually
worsen the heartburn by relaxing the lower esophageal sphincter.
Peptic ulcer should be treated with dietary modification and non-systemic antacids.
Sucralfate which is not absorbed, H2 receptor blockers and bismuth subsalicylate are safe
during pregnancy. H2 receptor blockers can also be used to treat GERD.
Constipation generally responds to high fibre diet, plenty of liquids and a mild laxative
such as milk of magnesia, docusate sodium, glycerin, mineral oil or bisacodyl.
Antimicrobial drugs: Beta lactam antibiotics (penicillins and most of the
cephalosporins) are safe during pregnancy. Ampicillin achieves very high concentrations in
the fetal circulation and amniotic fluid and is very suitable for treatment of uterine
infections during pregnancy. Erythromycin base is safe but erythromycin estolate should
be avoided for fear of hepatotoxicity. Nitrofurantoin and methanamine mandelate are
considered to be safe during pregnancy. So are nystatin and miconazole; but ketoconazole
and 5-flucytosine should be avoided.
Aminoglycosides are ototoxic to the fetus and should be avoided; if one is needed to
treat a serious systemic infection in the mother, gentamicin or tobramycin should be
preferred. Tetracyclines damage the fetal teeth and bones and should be avoided. High
doses of tetracycline IV have been associated with serious hepatotoxicity in the mother.
Chloramphenicol is absolutely contraindicated during pregnancy; it can cause fetal bone
marrow toxicity and ‘grey baby syndrome’ in the neonate. Cotrimoxazole should be
avoided especially in the 1st trimester (because of its trimethoprim content) and the 3rd
(because of its sulfonamide content). If there is anaerobic infection, metronidazole is considered
to be safe. Griseofulvin and nalidixic acid are embryotoxic and should be avoided. The use
of sulfonamides at term can cause kernicterus in the neonate by displacing bilirubin from
binding with albumin; aspirin, and water soluble vitamin K analogues can also displace
bilirubin from albumin.
Tuberculosis: Isoniazid and ethambutol are safe during pregnancy. Rifampicin should be
avoided as far as possible but may be used if a third drug is required. While using
rifampicin, its hepatatoxicity should be kept in mind. Streptomycin is ototoxic to the fetus and
should never be used in pregnant women.
Parasitic diseases: Amoebiasis is treated with the usual drugs: metronidazole, diodoquin
and diloxanide. However, large dose, short term therapy (e.g. single daily doses of 30
mg/kg with metronidazole) should be avoided.
Primaquine, is contraindicated throughout the pregnancy. Pyrimethamine and mefloquine
should be avoided in 1st trimester but appear to be safe in 2nd and 3rd trimester. Chronic
suppressive use of chloroquine weekly and its use to treat acute attacks of malaria during
pregnancy are safe. Quinine may be used to treat acute attacks of chloroquine-resistant
falciparum malaria.
Piperazine, bephenium and pyrantel are safe for use during pregnancy. Most people
consider mebendazole unsafe during pregnancy. Unless the parasite load is heavy, the
treatment of intestinal parasitic infections is best postponed till after delivery.
NSAID: Aspirin is not teratogenic but high dose aspirin treatment during the last 3
months is associated with increased gestation time, higher incidence of postmaturity and
prolonged labour. Further, it can also cause serious post-partum haemorrhage and
bleeding in the neonate. NSAID induce premature closure of ductus arteriosus with
pulmonary hypertension in the fetus and the newborn. Aspirin and NSAID are, therefore,
better be avoided during pregnancy, especially close to term. Paracetamol in the usual
doses is safe during pregnancy.
Glucocorticoids: Chapter 66.
Antihypertensives: Methyl-dopa is usually safe and preferred. Labetalol IV may be used
when rapid reduction in BP is desired. However, beta blockers in the second and third
trimesters can cause general retardation, whereas ACEI and ARB can cause fetal
abnormalities of renal function and skull development. These drugs probably interfere
with the maturation of specific organ systems (Chapter 30).
Heart disease: This is treated as in non-pregnant women. Digoxin clearance by the
kidney increases during pregnancy. If the dosage remains unchanged by the end of
pregnancy, the serum concentration will have fallen to about half the value before
pregnancy.
At the therapeutic concentration, quinidine appears to be safe and the drug has only
mild oxytocic activity. Quinidine is normally 80% bound to plasma protein. Changes in
plasma protein concentration during pregnancy cause total plasma quinidine
concentrations to fall and free concentration to be underestimated. After delivery, total
concentration of quinidine increases by about half.
Vasopressor agents (noradrenaline, dopamine and dobutamine) all decrease the uterine
blood flow and may stimulate uterine contractions. Their use in pregnancy is justified only
if the mother ’s survival is at stake.
Anticoagulants: Warfarin is best avoided in pregnant women, except those who have an
artificial heart valve; in these latter subjects, heparin does not give adequate anticoagulant
cover. In other patients, subcutaneous heparin should be used if anticoagulation is
required. One dose of heparin should be omitted when labour is imminent, so as to avoid
post-partum hemorrhage.
Deep vein thrombosis may be treated with heparin. The use of streptokinase is
associated with the risk of bleeding.
Allergic rhinitis: This may be treated either locally (with glucocorticoids or
decongestants) or systemically with antihistaminics (diphenhydramine, dimenhydrinate,
tripelenamine).
Cough: Diphenhydramine, codeine and dextromethorphan may be used safely to treat
dry cough during pregnancy.
Pruritus: This may be treated locally with topical moisturising creams or lotions e.g.
calamine lotion, zinc oxide cream or ointment or glucocorticoids; or systemically with
hydroxyzine, diphenhydramine or glucocorticoids.
Bronchial asthma is treated with inhaled beta adrenergic agonists, inhaled
glucocorticoids, or with aminophylline. However, IV salbutamol used to delay labour is
known to cause pulmonary edema especially (a) in individuals with mitral stenosis and (b)
when corticosteroids are administered concurrently to promote fetal lung maturation. The
combination may result in fetal death. This therapy should not be used in hypertensive
subjects. Further, in diabetic subjects IV salbutamol can cause severe hyperglycemia and
ketoacidosis, resistant even to aggressive insulin therapy.
Headache may be treated with paracetamol, codeine and benzodiazepines. Aspirin and
NSAID may be used in the first and second but avoided in the third trimester.
Migraine may be treated with analgesics, propranolol, dimenhydrinate and
amitryptiline.
Diabetes mellitus should be treated with dietary restriction and insulin, if required; the
use of oral hypoglycemic agents is not recommended. In insulin dependent diabetics who
become pregnant, the insulin requirement drops somewhat during the first trimester
(owing to nausea and poor food intake), then rises progressively to 2-3 times the pre-
pregnancy level upto 36 weeks, and then drops again upto term. After delivery, insulin
requirement dives dramatically to pre-pregnancy level.
Thyrotoxicosis: Thioamides are the therapy of choice for thyrotoxicosis during
pregnancy; propylthiouracil may be preferred to carbimazole/methimazole. The dose
should be kept as low as possible. Stable iodine and radioactive iodine are contraindicated
(Chapter 63).
Epilepsy: Adequate seizure control is important during pregnancy as convulsions
themselves are harmful to the fetus. Phenobarbitone, phenytoin and carbamazepine may
be used during pregnancy; as discussed earlier, their doses may have to be increased
slightly in order to maintain seizure control. All pregnant women on antiepileptic drugs
should be prescribed folic acid 5 mg per day throughout pregnancy. Vitamin K1 should be
administered to such patients routinely for 3 weeks before delivery and to their newborn
babies at birth. The use of valproic acid is contraindicated during pregnancy.
Drugs acting on the CNS: Barbiturates, benzodiazepines and antidepressants have not
been shown to have any significant teratogenic effects. Lithium has been reported to be
teratogenic and also to be deleterious to the fetus in the last trimester.
The use of CNS depressants such as diazepam, antidepressants, phenothiazines and
opioids at term and specially during labour, exposes the neonate to the risk of serious CNS
depression.
Benzodiazepines are best avoided towards the end of pregnancy.
Phenothiazines, tricyclic antidepressants and SSRI (except paroxetine) can be continued
during pregnancy in minimum possible doses. Antiparkinsonian drugs, e.g. benzhexol
commonly prescribed together with phenothiazine, should not be used during the first
trimester. MAO inhibitors are contraindicated during pregnancy. Further, it is desirable to
taper and omit tricyclic antidepressants in the last few weeks of pregnancy and to restart
them after delivery.
Breast Feeding and Drugs
Nearly all agents received by the mother are likely to be found in her milk and could
theoretically harm the infant. However, the data on excretion of drugs in milk and its
possible harmful effects on the newborn are scanty.
Breast feeding is important not only from nutritional point of view but it also supplies
IgA and IgM immunoglobulins which afford protection against gastroenteritis. More and
more women are now electing to breast feed their babies. Although several drugs are
known to increase prolactin secretion, no suitable drug is available at present, which could
consistently augment the milk production in the human female. Thyrotropin releasing
hormone (TRH) and metoclopramide have been shown to increase milk production in
some studies. However, it appears that determination on the mother ’s part is more
important than prolactin-inducing drugs. Lactation will stop if the breast is not suckled.
Suckling stimulates the release of prolactin and oxytocin.
Most of the lipid soluble drugs get into breast milk, though not necessarily in
concentrations that can adversely affect the infant. Milk is slightly more acidic (pH 7.0)
than plasma and hence, weak bases that become more ionised with decrease in pH will
have equal or higher concentrations in milk than in plasma. Nonelectrolytes like alcohol
(ethanol) can readily enter into the milk independently of the pH. Majority of the drugs get
into the milk by passive diffusion although active transport may occur in a few cases e.g.
iodide. The amount of a drug transferred into the milk depends on various factors. The
maternal volume of distribution for lipid soluble drugs is larger than for water soluble
drugs; this results in low plasma levels relative to the dose. Further, only the unbound
drug in the plasma is able to diffuse into the milk. Highly protein bound drugs such as
warfarin cannot be detected in breast milk. Even for a lipid soluble, poorly protein bound,
basic drug the milk to plasma ratio does not exceed four. Hence, drug toxicity based on the
principal pharmacological action of the drug is considered unlikely in breast fed infant.
However, toxicity based on idiosyncrasy or a particular sensitivity of the infant to very low
doses of a drug may occur.
The available data suggest that the net transfer of most drugs in breast milk is too small
to produce significant adverse effect in the breast fed infant. However, in view of such a
possibility, drugs, particularly the newer ones, must not be prescribed during parturition
unless essential. It must be remembered that the elimination rate for most drugs is slower
in neonates than in the adults and this may lead to accumulation of the drug in neonates,
particularly when it is taken for long courses by the mother.
Table 80.5 gives a list of the drugs not recommended during breast feeding. Aspirin and
paracetamol have been used extensively in the puerperium without apparent ill effects on
the infant. Heparin and warfarin are not detected in the milk. There is no contraindication
to thyroxine treatment for hypothyroidism during breast feeding. But, breast feeding
should be discouraged in women taking antithyroid drugs. Radioiodine is absolutely
contraindicated during breast feeding. Since most of the antibiotics pass into breast milk, it
may be advisable to avoid drugs like chloramphenicol, tetracycline and sulfonamides in
breast-feeding women. Penicillins, erythromycin, lincomycin, quinine and chloroquine
appear to be safe for the treatment of nursing mothers. Aminoglycoside antibiotics,
though they appear in breast milk, are not considered dangerous as they are not absorbed
from the gut. Metronidazole is considered quite safe during breast feeding but may make
the milk taste bitter. Beta-blockers, thiazide diuretics, captopril and digoxin levels achieved
in breast milk are probably too low to have any significant effect on the breast fed infants.
All centrally acting drugs, being lipid soluble, have a high volume of distribution. Hence,
the total amount of drug available for concentration in the milk is likely to be small. Opiate
analgesics, phenothiazines, chloral hydrate and antiepileptics may, therefore, be used
safely by the mothers, if necessary. However lithium has a high milk to plasma ratio and
the dose available to breast fed infant is likely to be similar to that of the mother; it should
be avoided during breast-feeding. Regular use of opioids in high doses by the mother may
lead to dependence and withdrawal in the neonate. Ergotamine may lead to ergotism and
chloroquine in the treatment of rheumatoid arthritis may cause retinal damage in the
newborn infant. Amiodarone is present in the milk in significant quantities; it is best
avoided because of the possible effects of the released iodine on the neonatal thyroid. The
neonate has been reported to become irritable when the breast feeding mother is taking
ephedrine, or 200 mg or more of aminophylline every 6 hours; slow release preparations of
aminophylline are probably safe. High levels in breast milk have been reported for the H2
blocker, cimetidine. Cytotoxic drugs, in general, are absolutely contraindicated in mothers who
are breast feeding.

Table 80.5
Drugs to be avoided/not recommended in breast feeding women

It should be realised that certain chemicals like DDT or methyl mercury acquired
environmentally, could appear in milk and cause chronic toxicity in breast fed babies.
Finally, if a drug is used therapeutically in the neonatal period, one may use it safely in breast
feeding women.