Reproduction and Periparturient Care 0195-5616/86 $0.00 + .

20

Drug Therapy During Pregnancy and

in the Neonate

Mark G. Papich, D.V.M., M.S.,*

and Lloyd E . Davis, D.V.M. , Ph.D. t

The choice of drug therapy for the pregnant animal and neonate is
frequently a dilemma. Many factors must be considered to ensure a rational
decision. Physiologic differences exist between the pregnant and nonpreg-
nant animal that influence absorption, distribution, metabolism, and excre-
tion of drugs and other compounds (xenobiotics). These differences influence
the therapeutic effectiveness of drugs administered to the gravid female.
Most drugs cross the placenta, making the developing embryo or fetus
an unintentional recipient of drugs given during pregnancy. Adverse effects
of drugs on the developing conceptus may occur at any time during
pregnancy. On the other hand, deliberate induction of abortion may have
deliterious effects on the female. Differences in metabolism, excretion, and
distribution affect the pharmacology of drugs in the neonate. These factors
influencing the therapy of diseases during the neonatal period will be
discussed.

DRUG THERAPY DURING PREGNANCY:

EFFECT ON THE MOTHER

Physiologic and Pharmacokinetic Alterations in Pregnancy

During pregnancy, there may be decreased gastrointestinal motility
and decreased gastric acid secretion. This may decrease absorption of weak
acids and increase absorption of weak bases from the stomach. 2 1• 24 Delayed
gastric emptying due to reduced motility will delay the rate of absorption
of some drugs, whereas prolonged transit time through the intestine will

*Assistant Professor of Clinical Pharmacology, Department of Veterinary Physiological Sci-

ences, Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon,
Saskatchewan, Canada
tProfessor of Clinical Pharmacology, Clinical Pharmacology Studies Unit, University of Illinois
College of Veterinary Medicine, Urbana, Illinois

Veterinary Clinics ojN01-th America: Small Animal Practice-Vol. 16, No.3, May 1986 525
526 MARK G. PAPICH AND LLOYD E. DAVIS

increase the absorption of poorly soluble drugs. 17 In women, there is a

decrease in the protein binding of drugs because of decreased plasma
albumin and decreased protein-binding affinity during pregnancy. This
increases the volume of distribution for many drugs and causes lower
plasma drug concentrations during pregnancy. 17 • 21 • 25 Lower drug concen-
trations in the blood may also result from an increase in drug clearance. In
particular, there may be increased clearance of drugs that rely primarily
on renal mechanisms for their elimination. Increased cardiac output and a
subsequent increase in renal blood flow and glomerular filtration rate (GFR)
have been shown to be responsible for decreased serum concentrations of
some antibiotics in pregnant women. The creatinine clearance may be
increased by as much as 50 per cent in pregnant versus nonpregnant
animals. 24 • 25
Drugs that rely upon hepatic biotransformation (metabolism) may have
decreased plasma concentrations during pregnancy. High progesterone
concentration during pregnancy is thought to induce the hepatic microsomal
enzymes responsible for drug metabolism. Hepatic clearance of drugs that
are highly extracted may be increased as well because of increased blood
flow to the liver. 24• 32 The therapeutic significance of these renal and hepatic
changes has not been well documented in veterinary medicine, but one
should consider the possibility of subtherapeutic drug concentrations as a
cause for lack of response to standard doses. For example, in pregnant
women, increased doses of penicillin, cephalosporin, and aminoglycoside
antibiotics are necessary to achieve therapeutic blood concentrations be-
cause of increased renal clearance. A pregnant woman may require twice
the dose of gentamicin that a nonpregnant woman would require .25• 37
Plasma anticonvulsant and digoxin concentrations may also be lower,
occasionally resulting in subtherapeutic concentrations. This necessitates
an increase in the dose for some women and monitoring of plasma drug
concentrations. 6• 12• 17
Adverse Drug Effects on the Mother During Pregnancy
When a veterinarian administers a drug to a pregnant animal, the
concern is usually for the developing fetus; however, the mother may be
at an increased risk for adverse effects during this time as well. Tetracycline
has caused fulminating hepatic failure in pregnant females owing to inhi-
bition of protein synthesis and decreased lipoprotein formation. Accumu-
lation of fat within the hepatocyte and hepatic steatosis follow. 13• 14• 37• 46 The
liver changes appear to be dose-related and may be exacerbated by
decreased renal function. Administration of erythromycin estolate during
pregnancy has been associated with a reversible, cholestatic hepatotoxicity. 37
The mechanism is unknown. If antibiotic therapy is necessary during
pregnancy, we recommend that other salts of erythromycin (for example,
e. stearate, e. ethylsuccinate) or the penicillin or cephalosporin antibiotics
that have a low incidence of adverse effects be used.
Drugs Used to Induce Abortion
The veterinarian is ofte n asked to terminate unwanted pregnancies in
dogs and cats. The preferred treatment is ovariohysterectomy (OHE). If
DRUG THERAPY DURING PREGNANCY AND IN THE NEO NATE 527

for some reason an OHE is unacceptable, pharmacologic termination of

pregnancy may be considered. The drugs that have been used as abortifa-
cients are estrogens, prostaglandins, and corticosteroids.
Estrogens are the most widely used abortifacient drugs. The proposed
mechanisms of action for estrogens are a change in the oviductal or uterine
environment, alteration of the transit time through the uterine tubes, and
inhibition of implantation. 4 · 38 The recommended dose of estradiol cypionate
(ECP) in the dog is 20 J.Lg per kg, given intramuscularly once during days
3 to 5 of estrus or within 3 days of a mating. 38 The total dose should not
exceed 1.0 mg. The dose in a cat is a total of 0.25 mg, given once within
72 hours of mating. ECP should be used only once during estrus. Admin-
istration during diestrus, when the uterus is under the influence of
progesterone, is associated with an increased incidence of endometrial
hyperplasia and pyometra.
Bowen and colleagues 4 evaluated the efficacy of the estrogens used to
terminate pregnancy. Estradiol cypionate was tested at doses of 22 J.Lg per
kg and 44 J.Lg per kg, given as a single intramuscular injection during
different stages of the estrous cycle. The dose of 44 J.Lg per kg was efficacious
in terminating pregnancy when given during estrus or diestrus. However,
in bitches that received either dose during diestrus, the incidence of
pyometra was 25 per cent (2 of 8).
Another estrogen compound is diethylstilbesterol (DES). It may be
used within 24 to 48 hours after mating at a dose of 0.1 to 1.0 mg per dog,
given orally, for 5 days. lnjectible DES has been removed from the market.
Bowen and colleagues 4 also evaluated the efficacy of DES in terminating
pregnancy in the dog. They found that oral DES (75 J.Lg per kg for 7 days)
was not effective in terminating pregnancy, regardless of which stage of the
estrous cycle the treatment was initiated. Eleven of 12 bitches conceived,
despite DES thetapy.
Besides the increased incidence of pyometra, the most severe adverse
effect of estrogens is bone marrow toxicity. Estrogens can be toxic to bone
marrow stem cells and lead to leukopenia, thrombocytopenia, and fatal
aplastic anemia. 27 The incidence of bone marrow toxicity appears to be less
with DES. 38
Prostaglandins (PC), in particular PGF2"', have been used to induce
abortion, although they are not approved for use in the dog or cat.
Prostaglandin F 2"' is widely used in large animals for luteolytic therapy, but
its use in small animals as an abortifacient has not gained wide popularity
owing to the undesirable side effects. Vomiting, diarrhea, hypersalivation,
and abdominal pain have been observed. 10· 35 A dose that has been
recommended for abortion is 60 J.Lg per kg per day, given intramuscularly,
and divided two to three times per day for 3 days. 35
Shillie and colleagues39 reported on the use of a synthetic prostaglandin
(Synchrocept*) given at a dose of 20 J.Lg per kg, intramuscularly, in the
middle of gestation in dogs. Although luteolysis occurred in all bitches and
was followed by abortion, there were significant "moderately severe" side

*Synchrocept-Syntex Animal Health, Des Moines, Iowa.

528 MARK G. PAPICH AND LLOYD E. DAVIS

effects that included salivation, vomiting, defecation, and pain at the

injection site.
In the cat, PGF2"' has been used to terminate pregnancy after day 40
with no serious side effects. Two doses are given 24 hours apart at 0.5 to
1. 0 mg per kg. 38

DRUG THERAPY DURING PREGNANCY:

EFFECT ON THE CONCEPTUS

Placental Transfer of Drugs

Placental transfer of drugs has not been evaluated in small animals or
people because of technical (and ethical) problems. Therefore, we rely on
information gathered from studies performed in rodents, rabbits, goats, and
sheep.
Miller and colleagues29 pointed out that "there is no single placenta
which can be readily used as a model to define structural or functional
characteristics applicable to all species." The type of placentation can affect
the transport of drugs or chemicals from the mother to the fetus. On the
basis of the number of tissue layers interposed between mother and fetus,
the placentae of the dog and cat are characterized as endotheliochorial.
Other domestic species have been classified as epitheliochorial and syndes-
mochorial. 43 The number of layers through which materials must pass to
reach the fetus formed the "placental barrier" concept; however, it is now
clear that the number of intervening cell layers between maternal and fetal
circulation has relatively little bearing on the transport of molecules across
the placenta. 29 Transfer of drugs across the placenta is dependent upon the
following factors: 9 • 26• 29 (1) drug dose and frequency administered to mother;
(2) drug volume of distribution; (3) rate of drug elimination by the dam; (4)
drug plasma protein binding; (5) drug metabolism by the placenta; (6) blood
flow to placenta; (7) drug diffusion rate; and (8) aging of the placenta.
The diffusion rate across the placental membrane, in turn, is governed
by the laws that govern transport across any biological membrane, which
is described by Fick's Law: 1• 29
dQ KA (Cm- Cf)
Rate of diffusion across placenta = dt = X ,

where X = membrane (placental) thickness; K = diffusion constant; A

surface area of membrane; and Cm - Cf = the difference between maternal
plasma drug concentration and fetal plasma drug concentration (concentra-
tion gradient).
K, the diffusion constant, is a characteristic of the drug and is
determined by the molecule's lipid solubility. Lipid solubility is influenced
by ionization of the drug. Nonionized molecules diffuse across lipid mem-
branes more readily than ionized molecules. The pH of maternal fluids is
more alkaline than that of fetal fluids, resulting in a concentration of weak
bases (for example, atropine, chlorpromazine, epinephrine, propranolol) on
the fetal side of the placenta, whereas weak acids (for example, penicillin,
DRUG THERAPY DURING PREGNANCY AND IN THE NEONATE 529

ampicillin, aspirin, furosemide) cross the placenta very slowly, even in the
presence of a steep concentration gradient. 1• 24 • 45
The size of the molecule also influences the value of K; however, size
is usually not a critical factor, for most drugs by themselves have a molecular
weight less than 500. Drug-protein binding will greatly increase the size of
the molecule and decrease the transport across the placenta. Protein binding
of drugs is not necessarily equal in the fetus and mother, and in fact, there
are drug-protein binding differences even between pregnant versus non-
pregnant females. 1• 26• 45 For some drugs, fetal tissues such as liver, muscle,
and plasma may have higher tissue-binding affinities than maternal tissue
or placental membranes, resulting in concentration of the protein-bound
drug in the fetus. 29
It should be apparent from this discussion that there is no true
"placental barrier." The transfer of drugs across the placenta to the fetus is
dependent upon the same factors that influence transfer to molecules across
any biological membrane. The veterinarian should consider that any drug
administered to a female during pegnancy has the ability to cross the
placenta and could be expected to have systemic effects on the fetus.
Fetal and Embryo Susceptibility to Drug Effects
The production of a birth defect or fetal anomaly is defined as
teratogenesis and is dependent upon the following factors: 6 (1) the nature
of the drug; (2) the degree of transfer from mother to fetus; (3) duration of
exposure; and (4) stage of fetal development. The placenta is not present
early in gestation. The fertilized ova are free-floating and subject to changes
in the uterine fluid of the mother. In the bitch, the fertilized ova enters
the uterus 5 to 6 days after conception and implants in 15 days. In the
queen, these events take 4 days and 13 days, respectively.43 Before
implantation takes place, the dividing embryos are very sensitive to toxic
compounds in the uterine fluid . The end of the embryonic period is 20
days in the dog and 18 days in the cat. The most critical period of gestation
for teratogenic effects of drugs is from 8 to 20 days following mating in the
dog and 5 to 15 days in the cat. 15
Once placentation is established, a drug may pass to the developing
fetus via the umbilical vein and be rapidly distributed to the fetal tissues.
Thirty-four to ninety-one per cent of the venous flow may bypass the fetal
liver by the ductus venosus. This minimizes any hepatic "first-pass" effect
and may result in a high systemic peak concentration of a drug in the fetus.
First-pass hepatic metabolism appears to be negligible in the fetus , regard-
less of blood flow to the liver, because very little drug-metabolizing activity
exists in the fetal liver of domestic animals. 45 This is in contrast to the
human fetus, which is capable of some hepatic drug oxidation reactions as
early as 5 to 6 weeks after conception. 20 Drug metabolites that may be
produced in the human fetus, but not in experimental animals, have
aroused concern over the validity of teratology testing in experimental
animals for drugs that are intended for use in people .5 • 20 This was illustrated
by the thalidomide tragedy in the late 1950s, in which the teratogenic
compound was a metabolite of thalidomide, which was produced by human
fetuses but not by experimental rodents.
530 MARK G. PAPICH AND LLOYD E. DAVIS

Adverse Effects of Drugs in the Embryo and Fetus

The potential adverse effects of drugs on the fetus have been examined
thoroughly in laboratory animals but not in domestic animals or in man.
Table 1 lists drugs that are contraindicated during pregnancy because of
their potential adverse effects. Table 2 contains drugs that have not been
proven to be safe but that are not necessarily contraindicated, and Table 3
contains a list of drugs that are safe for use during pregnancy. A few of the
examples are discussed below.
Antibiotics. Antibiotics are the most likely group of drugs to be
administered to a pregnant animal. Fortunately, most antimicrobials have
been found to be safe for use during pregnancy (see Table 3). Because beta-
lactam antibiotics (penicillins and cephalosporins) inhibit bacterial cell-wall
synthesis, they have no toxic effect on eukaryotic cells, nor do they
concentrate on the fetal side of the placenta. They are the safest antibiotics
to use during pregnancy. 37 Antibiotics that inhibit protein synthesis should
be avoided. In particular, one should not administer the aminoglycosides,
tetracyclines, or chloramphenicol (see Table 1). Tetracyclines may be toxic
to the mother, as well as disrupt fetal bone and tooth development. 25
Aminoglycosides (for example, gentamicin, amikacin, streptomycin) have
been associated with ototoxicity and nephrotoxicity. Sulfonamides should
be avoided during pregnancy because they compete with bilirubin binding
sites in the fetus and may cause neonatal hyperbilirubinemia.
Corticosteroids. Dexamethasone has been shown to cause fetal resorp-
tion and/or abortion when given to pregnant Beagles. 38 Corticosteroids have
been associated with the development of cleft palate in puppies. Cortisone
and prednisone have relatively lower incidences of this anomaly in compar-
ison with other corticosteroids. On this basis, it would be best to use only
these corticosteroids if steroid therapy is absolutely necessary during
pregnancy. 14
Anticonvulsants. Some anticonvulsant drugs have been associated with
congenital anomalies and neonatal hemorrhage in people; however, similar
problems have not been well documented in small animals. If a pregnant
animal has a seizure disorder that requires anticonvulsant therapy, it is
better to continue the anticonvulsant drugs than to risk status epilepticus.
Therapy should be cautious, and veterinarians must be aware of the possible
occurrence of subtherapeutic plasma concentrations of anticonvulsant drugs
in the mother, which may lead to an increased frequency of seizures during
pregnancy. 12 • 17
Anesthetics. Use of anesthetic drugs should be avoided during preg-
nancy. If anesthesia is necessary, one should avoid injectable agents that
require hepatic metabolism for elimination. Anesthetic management for
cesarean section is covered in the article "Cesarean Section."
Drug Transfer into Milk
Transfer of drugs into milk has been extensively studied in cows and
in women. Similar information on dogs and cats is lacking. Just as all drugs
have the potential for crossing the placenta, all drugs have the potential of
being excreted into the milk and having effects on the nursing puppy or
DRUG THERAPY DURING PREGNANCY AND IN THE NEONATE 531

Table 1. Drugs Contraindicated During Pregnancy*

DRUG ADVERSE EFFECTS

Antimicrobials
Chloramphenicol Fetal death
Nitrofurantoin Fetal hemolysis
Streptomycin Ototoxicity, congenital anomalies
Gentamicin Nephrotoxicity, otoxicity
Amikacin Ototoxicity
Tetracycline Altered bone and tooth development
Trimethoprim Teratogenic
Sulfonamides Liver dysfunction, hyperbilirubinemia
Amphotericin B Congenital anomalies
Griseofulvin Congenital anomalies
Fluocytosine Congenital anomalies
Erythromycin estolate Liver disease in dam
Metronidazole Mutagenesis in lab animals
Anti-inflammatory Drugs
NSAID (aspirin, phenylbutazone, Pulmonary hypertension, premature
indomethacin) closure of ductus arteriosus, prolongs
onset of labor, neonatal bleeding,
nephrosis
Glucocorticoids Cleft palate
Dimethyl sulfoxide Congenital anomalies
Anticonvulsants
Phenobarbital Hemorrhage in newborn
Primidone Hemorrhage in newborn
Phenytoin Congenital anomalies
Diazepam Neonatal depression
Antineoplastic Drugs
All Fetal death and anomalies
Cytotoxic drugs Fetal death, malformation
Propylthiouracil Neonatal goiter
Diazoxide Diabetes mellitus
Miscellaneous
Androgens Masculinization of female fetus
Acetazolamide Fetal anomalies
Anticoagulants Bleeding
Chlorpromazine Hepatic necrosis, fetal tachycardia
Cholinesterase inhibitors Neonatal myasthenia
Cyclizine Congenital anomalies
EDTA Congenital anomalies
Estrogens Feminization, abortion
Gold salts Congenital anomalies
Iodides Fetal goiter
Isoproterenol Fetal tachycardia
Lithium salts Fetal goiter
Mepivacaine Fetal bradycardia
Meclizine Congenital anomalies
Methoxamine Fetal hypoxia
Meperidine Patent ductus arteriosus
Prochlorperazine Congenital anomalies
Propranolol Hypoglycemia, fetal bradycardia
Phenylephrine Fetal hypoxia
Quinine Thrombocytopenia
Reserpine Respiratory obstruction
Thiazides Fetal death
Tolbutamide Hypoglycemia
Vitamin A (large doses) Fetal anomalies
Vitamin D (large doses) Hypercalcemia, CNS dysfunction
Vitamin K Hyperbilirubinemia
*References 1, 3, 6, 12, 14, 19, 25, 36 and 37.
532 MARK G. PAPICH AND LLOYD E. DAVIS

Table 2. Drugs that Have Not Been Proven to Be Safe for Use During Pregnancy
but Are Not Necessarily Contraindicated
Acepromazine Hexylcaine Prednisolone
Aminopromazine Hydralazine Procainamide
Aminopentamide Hydrocortisone Proparacaine
Arsenamide Propiopromazine
Iron dextran
Aspirin (early Pyrimethamine
pregnancy) Lenperone
Quinacrine
Levamisole
Bithionol Quinidine
Liothyronine
Bunamidine
Ronnel
Butorphanol Methylprednisolone
Meprobamate Saffan
Caffeine Spectinomycin
Methocarbamol
Chlorprothixene
Methoxyflurane Stanazolol
Cimetidine Styrylpyridium
Colchicine Neostigmine
Cortisone Nitroglycerin Thiabendazole
Cythioate Nitroprusside Thyroxin
Nystatin Toluene
Dapsone
Trichlorfon
Dichlorophene Phenoxybenzamine
Trifluomeprazine
Dithiazanine Phthalofyne
Trimethoprim
Dobutamine Physostigmine
Prazosin Xylazine
Fentanyl-droperidol Prednisone
Glycobiarsol
Note: Drugs included in this table have been responsible for congenital malformations in
one species of laboratory animal, or there is no information concerning their use during
pregnancy. (From Davis, L. E.: Veterinary Clinical Pharmacology. Philadelphia, W. B.
Saunders Co., [in press]; with permission. )

kitten. The pH partition hypothesis applies well to drugs passing into the
milk. Milk has an acidic pH relative to serum (6.5 to 7.2 versus 7.4), and
one would expect that drugs that are weak bases (for example, erythromycin,
trimethoprim/sulfa, aminoglycosides) will preferentially concentrate in the
milk. 2 · 6 Serious adverse effects associated with the transfer of drugs into
milk have not been reported in nursing animals. Nevertheless, veterinarians
should use caution in administering drugs su·ch as anesthetics, barbiturates,
cathartics, and potentially harmful antibiotics to the nursing mother.

DRUG THERAPY IN THE NEONATE

Drug Distribution in the Neonate Versus the Adult

Neonatal ruminants, swine, and human infants have been extensively
studied with respect to their ability to absorb, metabolize, and excrete
xenobiotics, but there is little information about neonatal small animals.
There are important differences between the neonate and the adult with
respect to drug metabolizing enzymes, drug absorption, drug distribution,
renal drug excretion, maturation of drug receptors, protein binding, and
the integrity of the blood-brain barrier. 40
Drug Absorption. Topical absorption in a neonate is enhanced because
of decreased integrity of the skin in the early weeks of life and a thinner
DRUG THERAPY DURING PREGNANCY AND IN THE NEONATE 533

Table 3. Drugs that Have Been Shown to Be Safe for Use During Pregnancy
Acetylcysteine Dimenhydrinate Methohexital
Amoxicillin Diphenhydramine Miconazole
Ampicillin Disophenol Morphine
Atropine Doxapram
Niclosamide
Ammonium Doxylamine
Nitrous oxide
chloride Enflurane Oxytocin
Cephalexin Ephedrine
Cephaloridine Ethrane Penicillin
Cephalothin Pilocarpine
Furosemide
Chloramphenicol Piperazine
(last half of Glycopyrrolate Pralidoxime
gestation only) Guaifenesin Procaine
Chlorpheniramine Halothane Pyrantel
Chymotrypsin Pyrilamine
Heparin
Clindamycin Salbutamol
Clonazepam Kanamycin
Ketamine Spironolactone
Codeine Sulfonamides (not
Cromolyn Lidocaine long-acting)
Colistin Lincomycin
Tetracaine
Dextromethorphan Mannitol Theophylline
Dichlorvos Mebendazole Thiopental
Dicloxacillin Metaproterenol Tiletamine
Diethylcarbamazine Methapyrilene Triamterene
Diethyl ether Methenamine
Digitoxin Urokinase
Digoxin
Note: Drugs included in this table were studied for teratogenicity in laboratory animals
with negative results. There have been no reports of deleterious effects resulting from these
drugs when administered during pregnancy. (From Davis, L. E. : Veterinary Clinical Phar-
macology. Philadelphia, W. B. Saunders Co. in press; with permission.)

hair coat. The topical administration of drugs and topical exposure to

environmental contaminants can result in increased blood levels of com-
pounds in a neonate. One should also consider oral absorption by licking
of topical compounds applied to the dam or siblings.
Gastric juice is usually less acidic in a neonate than an adult, 30 and
during that time there may be increased bioavailability of drugs that are
usually degraded by the gastric acid. 47 Large molecules such as immuno-
globulins are absorbed by the intestinal epithelium early in life. Although
drugs are rarely administered at this early age, absorption of drugs may be
increased. This characteristic of increased absorption diminishes signifi-
cantly 24 hours postpartum. 44
Any drug administered parenterally, particularly by the intramuscular
route, will be absorbed faster in the neonate than in the adult. This can be
explained by the increased total body water in the neonate (see following
section) and a decreased ability to sequester any material administered by
a parenteral route.
Drug Distribution. In man and some domestic animals, the extent of
drug distribution, measured as volume of distribution (Vd), is larger in a
neonatal animal than an adult. This was shown in pups, kids, pigs, and
foals in which the apparent specific volume of distribution for salicylate was
534 MARK G. PAPICH AND LLOYD E. DAVIS

larger in the newborn animal and decreased from birth to 30 days postpar-
tum.16 The greater volume of distribution is largely explained by greater
total body water of the neonate in comparison to an adult. Total body water
in an adult person is approximately 55 per cent of body weight, considerably
less than the 70 per cent found in a normal, full-term infant, and 85 per
cent in a premature infant. 6 In the puppy, total body water is 80 per cent
of body weight versus 60 per cent in the adult. 34 Peak serum concentration
of drugs usually correlates inversely with the volume of distribution. In the
neonate, this results in a lower plasma drug concentration, especially for
highly polar drugs that are limited in their distribution to the extracellular
space. 1s. 3o, 40. 47
Drug-protein binding may also influence the volume of distribution of
drugs in the neonate. Decreased plasma protein binding for a drug will
tend to restilt in an increased volume of distribution and lower plasma drug
concentrations. This may be offset by the property that only free (nonprotein
bound) drugs are able to exert pharmacologic effects. As a result, the
greater free fraction of total drug enhances pharmacologic or toxic drug
effects. In domestic animals, the lower drug-protein binding is a result of
lower plasma albumin in the neonate. Albumin does not reach adult values
for 2 to 3 weeks. 40 In people, there is a reported decrease in albumin
concentrations and qualitatively different albumin, which results in lower
drug plasma protein binding. 3· 30 This has been a point of disagreement,
however, as other authors report higher plasma albumin concentrations and
more extensive drug-protein binding in human neonates when compared
with adults. 26• 31
Drug Metabolism. The immature kidney and liver of the neonate
contribute to the differences in drug concentrations in the blood between
neonates and adults. Drug metabolism by the liver has been studied
extensively in the pig, ruminant, laboratory rodent, and infant, and we can
use that information to arrive at some generalizations for other species. is. 28
The pig was found to be almost totally deficient of the drug-metaboliz-
ing enzyme P-450 at birth. The P-450 microsomal enzymes increase
gradually up to 30 days of age and at day 30 are almost at the same level
of activity as an adult. 41 The metabolic reactions that have been identified
as deficient in the neonate are the mixed-function oxidases, UDP transfer-
ase, and conjugation with glucuronic acid. 40· 41 In the pig, the greatest rate
of increase in activity of these enzymes occurs during the first 3 to 4 weeks
postpartum and reaches near-adult activity by 6 weeks of age.
Decreased drug-metabolizing activity has also been demonstrated in
the calf. Chloramphenicol, an antibiotic that requires hepatic metabolism
for its elimination, was shown to have prolonged elimination for the first 4
to 6 weeks of life.
Davis and colleagues16 studied the metabolism of salicylate in puppies
and found the time required for maximal development of microsomal
enzymes was similar to other animals (30 days).
Renal Drug Excretion. Nephron immaturity is another factor in the
inability of neonates to excrete drugs. Drugs that may have prolonged
clearance are those that depend upon renal excretory mechanisms for
elimination (for example, polar, nonmetabolized drugs). In people, the full
DRUG THERAPY DURING PREGNANCY AND IN THE NEONATE 535
development of drug excretion by the kidney occurs slowly and is below
adult capabilities for the first 6 to 12 months of life. 6 · 30• 47 Renal elimination
of drugs may occur through two routes: glomerular filtration and tubular
secretion.
Glomerular filtration, measured as insulin clearance, reaches adult
values in 2 days in the calf, and in 2 to 4 days in the sheep, goat, and man
but develops more slowly in the dog and rodent. Active tubular secretion,
measured as paraaminohippuric acid (PAH) clearance, develops rapidly (2
to 4 days) in the pig and calf but much more slowly in the dog. 22• 40 The
newborn calf has an appreciable ability to excrete penicillin G (which is
dependent upon tubular secretion) before it is 24 hours old. 42
Redistribution of glomerular blood flow in dogs changes dramatically
in the first 2 weeks of life. 23 As the puppy matures, a greater fraction of
total glomerular blood flow shifts from the inner cortical Quxtamedullary)
glomeruli to the outer cortical glomeruli. Impairment of renal elimination
of drugs appears to be critical only during the early days of life, and after
2 weeks, approaches adult levels. There have been no clinical reports in
the dog and cat describing toxicity in neonates due to reduced renal
elimination of drugs, but obviously, drug therapy in animals at this young
age is rare.
The redistribution of renal blood flow may have a protective effect.
Cowan and colleagues 11 studied the nephrotoxic effects of gentamicin,
which requires glomerular filtration for elimination, in neonatal puppies.
They found that the pharmacokinetics of gentamicin were not significantly
different among 10-, 20-, and 30-day-old puppies. In addition, the shift of
blood flow from the juxtamedullary nephrons to the cortical nephrons
appeared to have a protective effect in sparing cortical nephrons from
gentamicin nephrotoxicity. This is in contrast to the foal, which had an
increased risk of nephrotoxicity when given gentamicin. 33
We define the neonatal period for the dog and cat as approximately
the first 30 to 45 days. After this time, the hepatic and renal drug-
eliminating mechanisms can be expected to approach adult values. If
anesthesia is required during the neonatal period, inhalant anesthetics are
preferred. If parenteral anesthetics are used, avoid anesthetics that require
extensive hepatic biotransformation (for example, barbiturates) or renal
excretion (ketamine). Also avoid sedatives, such as phenothiazine tranquil-
izers, that may have prolonged depressant activity and undesirable alpha-
adrenergic receptor blockade. Opiate drugs have the advantage of being
easily reversible and may be used without causing serious problems. An
extensive review of pediatric anesthesia has appeared elsewhere. 34
Bacterial infections can be particularly complicated in neonates because
of the immaturity of the immune system and an inability to localize
infections. 47 If antibiotics are to be employed, avoid those that have toxic
potential and require hepatic biotransformation for elimination, such as
chloramphenicol. Tetracycline should be avoided because of its antianabolic
effects and adverse effects on the development of bones and teeth. The
preferred antibiotics are the penicillins and cephalosporins, which exhibit
a high margin of safety and are bacteriocidal.
We recommend a conservative approach, following the guidelines
536 MARK G. PAPICH AND LLOYD E. DAVIS

established during studies done in the other domestic species. There are
large gaps in our knowledge, however, and species-to-species extrapolation
of scientific experiments can be dangerous. It is often better to rely on a
drug with a long history of safety rather than on questionable scientific
experiments.

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Department of Veterinary Physiological Sciences

Western College of Veterinary Medicine
University of Saskatchewan
Saskatoon, Saskatchewan
Canada 57N OWO