Testing of new drugs on animals for their effects
13 Carcinogens that are effective as a single dose in animals are known, e.g. nitrosamines.
on reproduction has been mandatory since the thalidomide disaster, even though the extrapolation of the findings to humans is uncertain (see Preclinical testing, p. 47). The placental transfer of drugs from the mother to the fetus is considered on page 98.
Drugs may act on the embryo and fetus:
Directly (thalidomide, cytotoxic drugs, antithyroid drugs, aromatic retinoids, e.g. isotretinoin): any drug affecting cell division, enzymes, protein synthesis or DNA synthesis, is a potential teratogen, e.g. many antimicrobials.
• on the uterus (vasoconstrictors reduce blood supply and cause fetal anoxia, misoprostol causes uterine contraction leading to abortion)
• on the mother's hormone balance.
Early pregnancy. During the first week after fertilisation, exposure to antimetabolites, misoprostol, ergot alkaloids or stilboesterol can cause abortion which may not be recognised as such. The most vulnerable period for major anatomical abnormality is that of organogenesis which occurs during weeks 2-8 of intrauterine life (4-10 weeks after the first day of the last menstruation). After the organs are formed, abnormalities are less anatomically dramatic. Thus the activity of a teratogen (teratos: monster) is most devastating soon after implantation, at doses which may not harm the mother and at a time when she may not know she is pregnant.
Drugs known to be teratogenic include cytotoxics, warfarin, alcohol, lithium, methotrexate, phenytoin, valproate, ACE inhibitors and isotretinoin. Selective interference can produce characteristic anatomical abnormalities, and the phocomelia (flipper-like) limb defect was one factor that caused thalidomide to be so readily recognised. (For an account of thalidomide see p. 81.)
Innumerable drugs have come under suspicion. Those for which evidence of safety was subsequently found include diazepam, oral contraceptives, spermicides, and salicylates. Naturally the subject is a highly emotional one for prospective parents. A definitive list of unsafe drugs is not practicable. Much depends on the dose taken and at what stage of pregnancy. The topic must be followed in the current literature.
Late pregnancy. Because the important organs are already formed, drugs will not cause the gross anatomical defects that can occur when they are given in early pregnancy. Administration of hormones, androgens or progestogens, can cause fetal mascu-linisation; iodide and antithyroid drugs in high dose can cause fetal goitre, as can lithium; tetracyclines can interfere with tooth and bone development, angiotensin-converting enzyme inhibitors are associated with renal tubular dysgenesis and a skull ossification defect. Tobacco smoking retards fetal growth; it does not cause anatomical abnormalities in man as far as is known.
Inhibitors of prostaglandin synthase (aspirin, indomethacin) may delay onset of labour and, in the fetus, cause closure of the ductus arteriosus, patency of which is dependent on prostaglandins. It is probable that drug allergy in the mother can also occur in the fetus and it is possible that the fetus may be sensitised where the mother shows no effect, e.g. neonatal thrombocytopenia from thiazide diuretics.
The suggestion that congenital cataract (due to denaturation of lens protein) might be due to drugs has some support in man. Chloroquine and chlorpromazine are concentrated in the fetal eye. Since both can cause retinopathy it would seem wise to avoid them in pregnancy if possible.
Anticoagulants in pregnancy: see page 571.
Drugs given to the mother just prior to labour can cause postnatal effects: CNS depressants may persist in and affect the baby for days after birth; vasoconstrictors can cause fetal distress by reducing uterine blood supply; P-adrenoceptor blockers may impair fetal response to hypoxia; sulphonamides displace bilirubin from plasma protein (risk of kemicterus); anticoagulants can cause haemorrhage.
Babies born to mothers dependent on opioids may show a physical withdrawal syndrome.
Drugs given during labour. Any drug that acts to depress respiration in the mother can cause respiratory depression in the newborn; opioid analgesics are notorious in this respect, but there can also be difficulty with any sedatives and general anaesthetics; they may also cause fetal distress by reducing uterine blood flow, and prolong labour by depressing uterine muscle.
Diazepam (and other depressants) in high doses may cause hypotonia in the baby and possibly interfere with suckling. There remains the possibility of later behavioural effects due to impaired development of the central nervous system due to psychotropic drugs used during pregnancy; such effects have been shown in animals, including impaired ability to learn their way around mazes.
Detection of teratogens. Anatomical abnormalities are the easiest to detect. Nonanatomical (functional) effects can also occur, though it is not appropriate to use the term teratogenesis (see definition above). They include effects on brain biochemistry which may have late behavioural consequences.
There is a substantial spontaneous background incidence of birth defect in the community (up to 2%) so that the detection of a low-grade teratogen that increases the incidence of one of the commoner abnormalities presents an intimidating task. Also, most teratogenic effects are probably multifactorial. In this emotionally charged area it is indeed hard for the public and especially for parents of an affected child to grasp that:
The concept of absolute safety of drugs needs to be demolished ... In real life it can never be shown that a drug (or anything else) has no teratogenic activity at all, in the sense of never being a contributory factor in anybody under any circumstances. This concept can neither be tested nor proved.
Let us suppose for example, that some agent doubles the incidence of a condition that has natural incidence of 1 in 10 000 births. If the hypothesis is true, then studying 20 000 pregnant women who have taken the drug and 20 000 who have not may yield respectively two cases and one case of the abnormality. It does not take a statistician to realise that this signifies nothing, and it may need ten times as many pregnant women (almost half a million) to produce a statistically significant result. This would involve such an extensive multicentre study that hundreds of doctors and hospitals have to participate. The participants then each tend to bend the protocol to
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