A Textbook of Clinical Pharmacology and Therapeutics

FERTILIZATION AND IMPLANTATION

Animal studies suggest that interference with the fetus before
17 days gestation causes abortion, i.e. if pregnancy continues
the fetus is unharmed.

ORGANOGENESIS/EMBRYONIC STAGE

At this stage, the fetus is differentiating to form major organs,
and this is the critical period for teratogenesis. Teratogens cause
deviations or abnormalities in the development of the embryo
that are compatible with prenatal life and are observable post-
natally. Drugs that interfere with this process can cause gross
structural defects (e.g. thalidomidephocomelia).
Some drugs are confirmed teratogens (Table 9.1), but for
many the evidence is inconclusive. Thalidomidewas unusual
in the way in which a very small dose of the drug given on
only one or two occasions between the fourth and seventh weeks
of pregnancy predictably produced serious malformations.

FETOGENIC STAGE

In this stage, the fetus undergoes further development and
maturation. Even after organogenesis is almost complete, drugs
can still have significant adverse effects on fetal growth and
development.

• ACE inhibitors and angiotensin receptor blockers cause
  fetal and neonatal renal dysfunction.


• Drugs used to treat maternal hyperthyroidism can cause
  fetal and neonatal hypothyroidism.


• Tetracyclineantibiotics inhibit growth of fetal bones and
  stain teeth.


• Aminoglycosides cause fetal VIIIth nerve damage.


• Opioids and cocainetaken regularly during pregnancy
  can lead to fetal drug dependency.


• Warfarincan cause fetal intracerebral bleeding.


• Indometacin, a potent inhibitor of prostaglandin
  synthesis, is used under specialist supervision to assist
  closure of patent ductus arteriosus in premature infants.


• Some hormones can cause inappropriate virilization or
  feminization.
  
  
  • Anticonvulsants may possibly be associated with mental
    retardation.
  
  
  • Cytotoxic drugs can cause intrauterine growth retardation
    and stillbirth.
  
  
  
  

DELIVERY

Some drugs given late in pregnancy or during delivery may

cause particular problems. Pethidine, administered as an anal-

gesic can cause fetal apnoea (which is reversed with naloxone,

see Chapter 25). Anaesthetic agents given during Caesarean

section may transiently depress neurological, respiratory and

muscular functions. Warfaringiven in late pregnancy causes a

haemostasis defect in the baby, and predisposes to cerebral

haemorrhage during delivery.

46 DRUGS IN PREGNANCY

Table 9.1:Some drugs that are teratogenic in humans.

Thalidomide Androgens

Cytotoxic agents Progestogens

Alcohol Danozol

Warfarin Diethylstilbestrol

Retinoids Radioisotopes

Most anticonvulsants Some live vaccines

Ribavarin Lithium

Key points

• Fertilization and implantation, 17 days.


• Organogenesis/embryonic stage, 17–57 days.


• Fetogenic stage.


• Delivery.

THE MALE

Although it is generally considered that sperm cells damaged by

drugs will not result in fertilization, the manufacturers of griseo-

fulvin, an antifungal agent, advise men not to father children

during or for six months after treatment. Finasteride, an anti-

androgen used in the treatment of benign prostatic hyperplasia,

is secreted in semen, and may be teratogenic to male fetuses.

RECOGNITION OF TERATOGENIC DRUGS

Major malformations that interfere with normal function

occur in 2–3% of newborn babies, and a small but unknown

fraction of these are due to drugs. Two principal problems face

those who are trying to determine whether a drug is terato-

genic when it is used to treat disease in humans:

1. Many drugs produce birth defects when given experi-
   mentally in large doses to pregnant animals. This does not
   necessarily mean that they are teratogenic in humans at
   therapeutic doses. Indeed, the metabolism and kinetics of
   drugs at high doses in other species is so different from that
   in humans as to limit seriously the relevance of such studies.
   2.Fetal defects are common (2–3%). Consequently, if the
   incidence of drug-induced abnormalities is low, a very
   large number of cases has to be observed to define a
   significant increase above this background level. Effects
   on the fetus may take several years to become clinically
   manifest. For example, diethylstilbestrolwas widely
   used in the late 1940s to prevent miscarriages and preterm
   births, despite little evidence of efficacy. In 1971, an
   association was reported between adenocarcinoma of the