16.3 The phantom fetus
Teratogenic issues
The term ‘phantom fetus’ has been used to describe
the current apprehension regarding the use of drugs
in women of childbearing potential. This appre-
hension has dominated industrial, and institutional,
and private research. The thalidomide tragedy of
the 1960s – the 10 000 or so deformed children now
grown to adults – continue to haunt us. It must be
recognized that, despite careful animal testing, the
full potential for teratogenic activity of any drugs
in humans will only come to light once the drug is
in the marketplace, and then only when sufficient
multiple exposures have occurred in pregnant
patients and their fetuses. It is extremely unlikely
that deliberate drug testing in pregnant women will
ever become routine. However, in special circum-
stances, such as HIV-infected pregnant women, it
is justified to include them in appropriate clinical
studies. Current predictive animal screening can-
not give complete assurance that the potential for
teratogenicity will be uncovered in all cases. It
must be remembered that the then-current 1956
screens did not discover the teratogenicity of tha-
lidomide, nor the 16-year delayed hyperplasia and
neoplasia effects on the cervix and uterus offemale
adolescents exposed to stilbestrol (given to prevent
miscarriages during their mothers’ pregnancies).
Both historically and currently, the major deter-
mination of teratogenicity is made from findings
from animal screening; many agents have been
eliminated from further development, and only
rarely does teratogenicity become uncovered in
the marketplace. Nonetheless, it requires large
numbers of exposures before the more subtle
embryotoxic or teratogenic effects are found, as
was demonstrated most recently by the ACE inhi-
bitors, which had passed all the screens. Indeed,
these events may never be exposed. How could this
be? One must take into account the ‘background
noise’ level, the so-called ‘natural’ incidence of
cogenital abnormalities. By far the commonest is
Down’s syndrome, whose incidence is known to
increase with the age of the mother, although
nearly all other abnormalities appear not to
increase with maternal age, according to a recent
report (Wilson, 1973). Thus, a higher incidence of
‘typical’ drug-induced teratogenic effects serve as
an early alert. The commonest abnormalities most
frequently associated with drug exposure in the
first trimester are neural tube defects, cardiac and
renal anomalies, shortening of limbs and digits and
failure of closure of the palate and upper lip. More
subtle changes associated with exposure to drugs
occur in the third trimester, with hearing and eye
abnormalities predominating (Wilson, 1973). Any
such determinations require many, many thou-
sands of exposures before they become apparent.
However, many millions of women become
pregnant before being aware of their pregnancy
and have been exposed to environmental chemicals
(most of which have never been tested), as well as
OTC drugs and prescription drugs. Also, a number
of embryos are spontaneously aborted and a delay
to the menstrual period of perhaps two or three
weeks passes unremarked or sometimes unnoticed
in a background of a national miscarriage rate of
one in three pregnancies (Yoder, 1984). Teratolo-
gists have concluded that there is a threshold dose
for any drug before it shows potential teratogeni-
city(inother words,enoughmust begiven), and the
effect tends to increase with the duration of expo-
sure, with higher concentrations in the plasma or
tissues and with the timing of the developing
fetal tissues and organs (Wilson, 1973). In the
first seven to eight days, the embryo is refractory
to any teratogenic effect but is mostsusceptible
20–55 days after conception. Of some reassurance
is that most drugs prescribed to women of child-
bearing age are antibiotics and tend to be for rela-
tively short durations. But the tetracyclines and
antiepileptic drugs are known to have effects on
the developing fetus and are frequently prescribed
to women (Stewart, 1998).
It is an irony that the normal tenet of US and UK
law that an individual is ‘innocent until proven
guilty’does not apply to prescribed pharmaceutical
products or devices. They must be proven safe and
efficacious before they are approved; in other
words, they must beproven to be innocent.Thus,
it comes as no surprise that industry and other
research groups tend to avoid the potential expo-
sure of women of childbearing age in the early
clinical development of pharmaceuticals or206 CH16 DRUG DEVELOPMENT RESEARCH IN WOMEN