J. clin. Path., 29, Suppl. (Roy. Coll. Path.), 10, 150-156

Teratogens in the human: Current problemsD. F. HAWKINS

From the Institute of Obstetrics and Gynaecology, Hammersmith Hospital, London

Drugs administered to the mother can affect thefetus by preventing implantation or by causing re-sorption of the embryo, abortion or intrauterinedeath. It is a sobering thought that the first of thesemechanisms is dignified by the name 'contracep-tion' and that the remainder have far less medico-legal and economic significance than the survival of adefective fetus after a less drastic chemical orphysical insult (Law Commission, 1974).The general principles of teratogenesis in humans

have recently been reviewed by Lewis (1974). Themajority of drugs are of molecular weight below1000 and pass the placenta into the fetus. Their rateof transfer is enhanced by small molecular weight,lipophilic properties, and a high concentration ofnonionized drug, not bound to plasma protein, in thematernal circulation. Drugs for which detoxicationmechanisms, metabolic degradation or urinary ex-cretion are deficient in the fetus are more likely toaccumulate.The extent and nature of a teratogenic effect de-

pend on length of gestation. In general, agentsadministered before implantation either destroy theembryo or damage cells in the blastocyst which canbe replaced by undifferentiated cells which retaintotipotency. Maximum susceptibility in man isduring organogenesis, from the first week afterfertilization until the ninth week, that is, from threeto 11 weeks after the last menstrual period. The samestimulus may produce a different anomaly at differ-ent stages of gestation, depending on which organsare in a critical stage of development. Some agentsshow a predilection for causing abnormalities inparticular organ systems; sometimes this can be re-lated to a high local tissue concentration or specificinfluence on a particular metabolic pathway but inother instances the mechanism is unknown. Thegenetic constitution of the embryo has a major in-fluence on its response, and species differences arethe primary hindrance to the screening of agents inanimals for teratogenic potential and the interpreta-tion of the relevance of the results to humans. Even inman, racial and familial predisposition to particularanomalies may influence the nature of a teratogenicresponse.

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Recognition of a Teratogenic Effect

The likelihood that some drugs will cause fetal ab-normality can be predicted from knowledge of theirmode of action, their pharmacological and toxicactions, and their chemical similarity to known tera-togens. Primary testing of most new compoundswhich may be employed in human therapeutics takesplace in animals. Chick embryos and pregnant mice,rats and rabbits are widely used, employing parent-eral administration of maximum tolerated doses.Some teratogens will only be detected by the re-sponse of a single species; others will cause speciesspecific anomalies. Agents known to be innocuous inman, by virtue of many years of wide therapeutic usein pregnant women, sometimes have a teratogeniceffect when given in massive overdose in a selectedanimal test. On the other hand, whilst the animaltests are likely to detect a major teratogen, this is byno means certain. It is therefore desirable that alldrugs intended for widespread use in the pregnantfemale be tested in primates and then introduced in-to human therapeutics with extreme caution andclose monitoring. There are some situations whichare unequivocally life threatening to the motherwherea new drug can be reasonably employed, such as anew antibiotic in a serious infection which provesresistant to available medicaments.The other methods by which adverse effects on

fetal development can be detected are epidemio-logical. When the incidence of a given abnormalityis noted to be high or increasing in a community,careful retrospective analysis may reveal the cause.It was by this means that Lenz (1961) found therelationship between phocomelia and thalidomide.Such analyses are not immune from error-thecoincident onset of another source of fetal abnor-mality such as a virus epidemic apparently causingonly trivial symptoms can be misleading. In additionit is always possible that it is the disease which thedrug is used to treat, or an associated condition,that is the real predisposing factor. Retrospectivesurveys of the antecedents of a fetal condition ofknown and consistent incidence are even moresusceptible to such errors. They depend on the

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demonstration of correlations which may not haveany causal basis. Only when a relevant mode ofaction of the suspected teratogen in producing theabnormality in susceptible individuals has beendemonstrated can the case be regarded as proven as

far as those individuals are concerned. Retrospectivesurveys are nearly always biased by the enhancedrecall of mothers who have produced an abnormalbaby. Even prospective surveys are open to theproblem that it may be the disease and not the drugused to treat it that is the adverse factor. Only manyyears of extremely large-scale studies of carefullymatched and analysed cases will serve to determinethe true magnitude of the effect of drug therapyduring pregnancy in relation to congenital abnor-mality.

Major Teratogens in Man

These include thalidomide which characteristicallycauses phocomelia; actinomycin, folic acid anti-metabolites such as methotrexate, and alkylatingantimitotic drugs, which cause fetal death or a varietyof anomalies if the fetus survives; tetracycline whichdiscolours and causes enamel hypoplasia in decidu-ous teeth; and radioactive 131I which causes fetalgoitre. There are very few circumstances in whichthere is no alternative to the use of these agentsin pregnancy. If any of these agents, except tetra-cycline, is vital to the survival of the mother thenthe pregnancy should be terminated. Similar con-siderations apply to the use of irradiation of thepelvis or whole body to treat cancer or related condi-tions and to open-heart surgery with the use of a

bypass circulation which will cause prolonged fetalanoxia. In the last case, it must be remembered thatthe teratogenic effects of anoxia in early pregnancy,should the fetus survive, are well established ex-

perimentally.

Therapeutic Agents which may Convey a Small Riskto the Fetus

A number of drugs used in pregnancy in this classare shown in table I.When a patient for whom treatment with one of

these agents is indicated undertakes a pregnancy,

what is said to her and her attitude are of greatimportance. Any pregnant woman, on drug therapyor not, told of the calculated risk that her baby willbe abnormal will react adversely. Such a statementshows lack of perspective. If odds are required, thenthe patient wishes to know the chance that her babywill be normal. In conditions requiring treatmentwith the drugs indicated in table I, the patient isnearly always aware that there is some risk that herpregnancy may be unsuccessful. In general the majorhazard is the maternal disease itself, the chances ofdrug teratogenicity being small in comparison. Bothhazards are much reduced by careful clinicalmanagement and close control of drug treatment.For example, the patient who has had recurrent

pulmonary emboli in previous pregnancies may needanticoagulant therapy throughout a pregnancy.

With subcutaneous heparin in the first trimester,then a well controlled warfarin regimen until 38weeks, an intravenous heparin infusion for a fewdays, discontinued for elective induction of labour,careful management of the third stage of labour, andheparin and then warfarin in the puerperium, therisk to the fetus should be minimal. Similarly thethyrotoxic patient carefully managed with a com-

bination of partial thyroidectomy and then, ifnecessary, the small amounts of antithyroid drugsrequired to achieve a euthyroid status, should pose

only a tiny risk to the fetal thyroid. Close control oftherapy in maternal disorders such as essential hyper-tension, diabetes mellitus and conditions requiring

Antithyroid drugs; iodides Fetal goitreAzathioprine; mercaptopurine Susceptibility to virus infectionBarbiturates (large doses) Newborn withdrawal syndromeChloroquine Retinal damage; multiple abnormalitiesCoumarin anticoagulants Fetal haemorrhage; rarely, fetal abnormalitiesDiazepam and related benzodiazepines (large doses) Newborn withdrawal syndromeFrusemide Maternal intravascular dehydration and reduced placental perfusion

leading to fetal growth retardationGanglion blockers Paralytic ileusGlucocorticoids Susceptibility to virus infection; very rarely cleft palateLive vaccines Fetal virus infectionNarcotics Respiratory depression; newborn withdrawal syndrome19-Nor-steroids Virilisation of female fetus (transient clitoral hypertrophy; rarely labial

fusion)Phenytoin, primidone Fetal abnormalities, fetal bleeding; newborn withdrawal syndromeRauwolfia alkaloids Newborn depression syndromeStreptomycin, kanamycin, gentamicin, vancomycin Sometimes minor 8th nerve damage detected on audiometry, very rarely

deafnessVitamin D (large doses); dihydrotachysterol Skeletal abnormalities

Table I Some therapeutic agents believed to convey a teratogenic risk in a small proportion of cases

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steroid therapy in pregnancy should accomplish asatisfactory outcome to both mother and fetus.

Suspicions of Teratogenic Activity

Since the thalidomide disaster, many reports haveappeared in the medical literature based on suspicionalone (table II). All the fallacies havebeen incorporated-extrapolation from animal data, selected popula-tions, assumptions that a correlation means a causalrelationship, retrospective surveys and unsub-stantiated theory. Whilst it is highly desirable thatsuch suspicions should be aired at the earliest op-portunity, there are dangers when they are reiteratedas established fact. It has been said that far morebabies were damaged or lost in the years followingthe first reports on the risk of the use of radio-graphs in pregnancy from failure to radiographthan were ever at risk for leukaemia even if that riskwas as at first thought. Withdrawal of therapy froma pregnant epileptic is more likely to cause fetaldamage than its continuation with appropriate pre-cautions. The consequences of failure to treat evenminor conditions such as hyperemesis or tricho-moniasis could outweigh the potential hazards oftherapy.

Current Problems

SEX HORMONESIt has recently been suggested that the use of oralcontraceptives can predispose to congenital ab-normality. The work is based on retrospectivesurveys, with all their difficulties. The first suspicionis an association with limb reduction defects. This isa relatively rare malformation whose incidence inNew York State (0.25 per 1000 births in 1973) hasbeen rising in parallel with increased use of oralcontraceptives. Janerich et al (1974) found an in-creased proportion of mothers of such babies haddiscontinued oral contraceptives in the cycle im-mediately before conception, compared with controlseries. It is possible that this might be linked with the'aging ovum' situation. Ovulation is often delayed inthe first cycle and conception late in the cycle may belinked with congenital abnormalities (Cross, 1961;Iffy, 1963; Hertig, 1967). Also, it is not surprisingthat neonatal jaundice has been reported to beassociated with previous maternal use of oral con-traceptives. The ease with which the maturity of apregnancy may be underestimated and consequentlylabour inadvertently induced prematurely may bethe factor responsible. The association has not beenconfirmed in subsequent better controlled studies(Gould et al, 1974).

In addition, Janerich et al (1973) reported that six

D. F. Hawkins

of their 108 mothers of babies with limb reductiondefects had become pregnant whilst taking oralcontraceptives, and six more had been given sexsteroids during the pregnancy. It was a surprisingand perhaps significant finding that in every one ofthe mothers who had had oral hormones in earlypregnancy, the sex of the affected baby was male.Some support for the concept that sex hormoneadministration in early pregnancy may convey asmall teratogenic risk has come from Colorado,where Nora and Nora (1975) have described asyndrome of multiple abnormalities-vertebral,anal, cardiac, tracheo-oesophageal, renal and limbdeformities, which they feel may be associated. InEngland and Wales, Greenberg et al (1975) havesuggested that an increased proportion of mothersof abnormal babies have been given doses of hor-mones in early pregnancy in the form of 'oralpregnancy tests' to see if withdrawal bleeding occurs.

It has been known for years (Wilkins, 1960) that19-nor-progestagens given in early pregnancy cangive rise to a very minor degree of virilization in fe-male fetuses. When this occurs it is usually justclitoral hypertrophy which resolves over the firstyear of life, but occasionally fusion of the labio-scrotal folds requires division. More serious are thecluster of cases of adenocarcinoma of the vagina inteenage girls whose mothers had been given stilbo-estrol during pregnancy in the Boston area (Herbstet al, 1971). On the other hand, Kinlen et al (1974)were unable to pinpoint a single case amongst the12000 patients they estimated had been givenstilboestrol in Great Britain.The number of cases of fetal abnormality that

could possibly be attributed to sex hormones is smalland, in most instances, the case is unproven. Oralcontraceptive failure or administration of an oralpregnancy test do not qualify as a 'substantial risk'under the Abortion Act. With the oral contracep-tives the dose of hormones has now been reduced toa very low level. On the other hand there is no validindication for using oral pregnancy tests, and thereis no evidence that either stilboestrol or 19-nor-steroids have any value in pregnancy maintenance(Hawkins, 1974) and their use should be abandoned.Only with a woman suffering from primary habitualabortion who has demonstrable progesterone de-ficiency is there any case at all for hormone supple-ments, and 17-hydroxyprogesterone, which has notbeen indicted, is the most appropriate agent.

Antiepileptic Treatment

It is now clear that phenytoin and related agents cancause folic acid deficiency in pregnancy and, prob-ably in consequence, give rise to congenital ab-

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normalities in a small proportion of babies. In addi-tion, there is a risk of fetal bleeding during the con-

finement and the newborn babies are susceptible to asedative withdrawal syndrome. It is important thatepileptic women should plan their pregnancies andshould start taking folic acid supplements beforethey even conceive and continue throughout thepregnancy. This is in order that any necessary adjust-ment can be made to the dose of phenytoin and thatadequate folic acid is available during implantationand organogenesis. Parenteral vitamin K should begiven to the mother early in labour and the newbornclosely supervised in a neonatal unit for three daysafter delivery.With epileptics controlled on barbiturates, the

main risk is that of sedative withdrawal in the new-

born, which requires careful management (Desmondet al, 1972).

Sulphonamides

Experimentally, only sulphafurazole, long-actingsulphonamides and trimethoprim with sulphame-thoxazole have raised any suspicion of embryo-pathic activity. In practice there is no evidence ofteratogenicity in man, but as there are alternativesulphonamides, the first two are possibly bestavoided, and if trimethoprim with sulphamethoxa-zole is used in pregnancy folic acid supplementsshould be given.

In the newborn sulphonamides can compete for

AlcoholAmine oxidase inhibitorsAmphetaminesAntacids in first trimesterAntiemetics, cyclizineAspirin; phenacetinBarbiturates in ordinary dosesCannabis smokingChlorpromazine (large doses)ChlorthiazideIdoxuridineIron preparations in first trimesterLithium carbonateLysergic acid diethylamideMeprobamate in first trimesterMetronidazoleMethyldopa (large doses)Oral contraceptivesOral pregnancy testsOral hypoglycaemic agentsPodophyllinPropranololQuinineStilboestrolSulphonamidesTobacco smoking

Tricyclic antidepressantsX-ray exposure

binding sites for bilirubin conjugation and increaseplasma bilirubin levels. It has been suggested (Stirratand Beard, 1973) that the drugs are contraindicatedin pregnancy in that they could cause neonata,jaundice and kernicterus in the newborn. In factlalthough the drugs have been very widely used inpregnancy for many years, there is no evidence thatthis phenomenon ever occurs with short-actingsulphonamides. Kernicterus is extremely rare inGreat Britain, except in association with rhesus iso-immunization, and no cases connected with sulpho-namide therapy in pregnancy have been reported tothe Committee on Safety of Medicines. Oralsulphonamides are still the first line of attack forurinary infections in pregnancy; they are of no use inlabour due to poor absorption.

Metronidazole

Following a study by Rustiaand Shubik(1972), whichsuggested that mice fed on large doses of metroni-dazole throughout their lives had an increasedincidence of adenomata in the lung, and work byVoogd et al (1974) showing that the drug increasedthe mutation rate in certain bacteria, efforts were

made to ban the use of metronidazole entirely inthe United States of America. Its use to treattrichomoniasis in pregnancy has been criticized.Further animal studies have failed to confirmthat there is any carcinogenic or teratogenic riskassociated with metronidazole. In fact, over

Intrauterine and infant growth retardation; fetal abnormalitiesFetal abnormalities; perinatal deathFetal thrombocytopenia

Fetal abnormalities; fetal bleedingFetal abnormalities; minor skin malformations

Retinal damageFetal thrombocytopenia

Meconium ileusLimb and gastro-intestinal abnormalities; neonatal jaundiceLimb and other abnormalities, particularly in male fetusesFetal abnormalities; fetal hypoglycaemia and hypothyroidism

Intrauterine growth retardationFetal abnormalities; fetal thrombocytopenia; middle ear damageVaginal adenosis and adenocarcinomaFetal abnormalities; neonatal jaundicePrematurity, intrauterine growth retardation; increased perinatal mort-

alityFetal abnormalities; perinatal deathFetal abnormalities; infant leukaemia and malignant disease

Table II Some drugs on which suspicion has been cast'"Where no risk is indicated, an association with an overall increase in fetal abnormality has been suspected.

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6 500 000 women have been treated with metronida-zole and there has never been any suggestion ofcarcinogenicity. Over 2500 cases of women treatedduring pregnancy are reported in the medical litera-ture and no atypical incidence of congenital ab-normalities has been recorded. The major retrospec-tive surveys have failed to suggest any teratogenicassociation. It must also be taken into account thatvaginal trichomoniasis is commonly associated within-situ and invasive carcinoma of the cervix, and thatwomen with untreated trichomonal infections have atendency to go into premature labour of the typethat starts with rupture of the membranes.The evidence on metronidazole should be con-

sidered against the background that when the drugwas introduced as an oral agent in Great Britain 15years ago, its efficacy was rapidly recognized and itswept the market of all the relatively ineffective localtrichomonacides. The current criticisms have arisenin the United States of America within a year or twoof the introduction of oral metronidazole to theAmerican market.

In practice, avoidance of the use of oral metro-nidazole in pregnancy during the first 16 weeksshould relieve any doubts about its potential, thoughthe case is entirely unproven.

Barbiturates

Obstetricians have a justifiable scepticism aboutcriticism of the use of barbiturates. The drugs havebeen enormously widely used during pregnancy forover 40 years, with much benefit to the patients.Fifteen years ago suspicions were voiced that thedrugs caused liver damage in the newborn. Sevenyears ago we were advised that they stimulated for-mation of detoxifying enzymes in the fetal liver whichtended to protect the baby against birth asphyxiaand neonatal jaundice. Most recently (see BritishMedical Journal, 1972) we have been told of thepossiblity of generating behavioural abnormalitiesin the babies. Although barbiturates are used sowidely in pregnancy, the retrospective surveys areequivocal with regard to teratogenesis. The slightlyincreased incidence of abnormalities found byNelson and Forfar (1971) may well be accounted forby the complications of pregnancy for which barbi-turates were prescribed. Detailed analysis of thedata obtained in the Royal College of GeneralPractitioners' survey (1975) showed no suggestion ofa cause-and-effect relationship between barbituratetherapy and congenital malformations.

It seems reasonable to continue to use barbitu-rates in pregnancy in conditions where they are in-dicated, and perhaps preferable to prescribing newerdrugs about which less is known. The babies of

patients given moderate or large doses of barbitu-rates-or, for that matter, diazepam-up to theconfinement, should be observed for any signs of asedative withdrawal syndrome (Desmond et al,1972; Cree et al, 1973).

Tranquillzers

A number of antihistamines and phenothiazinesused in the treatment of morning sickness have beensuccessively indicted and cleared of suspicion. Thewidely used drugs, promethazine and its theophyl-line conjugate, have not been seriously questioned.Cyclizine and diphenhydramine are still under re-view and should probably be avoided.Though there is no clear evidence with respect to

monamine oxidase inhibitors and tricyclic anti-depressants, obstetricians do not like them andanaesthetists do not like them. The suspicion is therethat the baby which has been subjected to them inthe intrauterine environment is at risk, and mostpractitioners adopt a reactionary attitude when pre-scribing sedatives and tranquillizers for pregnantwomen.

Lysergic acid diethylamide can be teratogenic inexperimental circumstances. Isolated cases of con-genital abnormalities have been seen in women whotake drugs during pregnancy. It is difficult to obtainreliable histories and these cases could well be dueto other teratogenic factors. There is as yet nosignificant evidence with respect to the effects ofcannabis smoking on the fetus.

Alcohol

Attention has recently been drawn to a syndrome inthe newborn associated with alcoholism in preg-nancy (Jones et al, 1973; Jones and Smith, 1973).Microcephaly, skull malformations and other ano-malies can occur. More consistent are intrauterinegrowth retardation, infant growth retardation anddelayed behavioural development. The babies ofalcoholic mothers need careful observation andfollow up.

Tobacco Smoking

Since the first demonstration by Simpson (1957) of acorrelation between smoking in pregnancy and re-tarded intrauterine growth, a mass of evidence onthis correlation has built up (U.S. Department ofHealth, Education and Welfare, 1973). Commentsmade at the time (Hawkins, 1959)remain unanswered-no causal mechanism has yet been clearly demon-strated. It is quite clear that smoking in pregnancyis associated with small-for-dates babies, and theremay be an association with premature labour and

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perhaps with an increased perinatal mortality, thoughthe last has not been confirmed inlarge-scaleAmericanstudies. What is often said, but is quite unproven, isthat persuading women to stop smoking in pregnancyimproves the prognosis. The work of Butler et al(1972), who showed that women who reported ceas-ing to smoke after the fourth month had a normalprognosis for the baby, is really unhelpful. It is a

retrospective survey, susceptible to biased recall. Inaddition, women who stop smoking in pregnancy oftheir own volition are a special group who are ex-hibiting a pica. Women who are persuaded to stopsmoking in pregnancy are a totally different group.In a recently controlled prospective study conductedin three London teaching hospitals the usual asso-ciation was confirmed but it was shown that thosewomen who were persuaded to stop smoking did notachieve an improved prognosis (Donovan, J.,personal communication, 1975).The situation therefore harks back to the original

contention that there are a proportion of women

who have in common the attributes that they smokeand that they produce small babies!

Radiographs and Ultrasound

The recent publicity given to the desirability ofavoiding all but urgent radiological examinationsduring the second half of the menstrual cycle (RoyalCollege of Radiologists, 1975) to avoid any risk toan early conceptus is obviously reasonable. Similarlythe avoidance of non-essential radiographs inpregnancy, the precautions taken to minimize ex-

posure and the avoidance of examinations involvingmultiple exposures are sound practice. On the otherhand it must be recalled that the numerical risk tothe fetus is extremely small. In these circumstancesthe fact that a woman has inadvertently had a

radiological examination in early pregnancy cannotbe taken to constitute the substantial risk of physicalor mental abnormality in the baby which constitutesgrounds for terminating the pregnancy under theAbortion Act.Much play has been made in recent years of the

idea that many radiological examinations in preg-nancy could be replaced by the use of ultrasound. Itshould be borne in mind that whether or not ultra-sound examinations can have teratogenic long-termeffects on the fetus is quite unknown.

Conclusion

The practitioner who restricts his prescribing forpregnant women to circumstances where medica-tion is really indicated, and employs medicineswhich have been widely used in pregnancy for many

years without apparent harm is unlikely to contri-bute significantly to the incidence of congenitalmalformations.

References

British Medical Journal (1972). Neonatal behaviour andmaternal barbiturates. (Leading article). Brit. med. J., 4,63-64.

Butler, N. R., Goldstein, H., and Ross, E. M. (1972).Cigarette smoking in pregnancy: its influence on birthweight and perinatal mortality. Brit. med. J., 2, 127-130.

Cree, J. E., Meyer, J., and Hailey, D. M. (1973). Diazepam inlabour: its metabolism and effect on clinical condition andthermogenesis of newborn. Brit. med. J., 4, 251-255.

Cross, R. G. (1961). Prevention of anencephaly and foetalabnormalities by a preconceptional regimen. Lancet, 2,1124.

Desmond, M. M., Schwanecke, R. P., Wilson, G. S.,Yasunaga, S., and Burgdorff, I. (1972). Maternal barbitu-rate utilization and neonatal withdrawal symptomatology.J. Pediat., 80, 190-197.

Gould, S. R., Mountrose, U., Brown, D. J., Whitehouse,W. L., and Barnardo, D. E. (1974). Influence of previousoral contraception and maternal oxytocin infusion onneonatal jaundice. Brit. med. J., 3, 228-230.

Greenberg, G., Inman, W. H W, Weatherall, J. A. C., andAdelstein, A. M. (1975). Hormonal pregnancy tests andcongenital malformations. (Letter). Brit. med. J., 2, 191-192.

Hawkins, D. F. (1959). Birth weight and maternal smoking.(Letter). Brit. med. J., 2, 820.

Hawkins, D. F. (1974). Sex hormones in pregnancy. InObstetric Therapeutics, edited by D. F. Hawkins, ch. 3,pp. 106-150. Bailliere Tindall, London.

Herbst, A. L., Ulfelder, H., and Poskanzer, D. C. (1971).Adenocarcinoma of the vagina: association of stilbestroltherapy with tumor appearance in young women. NewEngl. J. Med., 284, 878-881.

Hertig, A. T. (1967). Human trophoblast: normal andabnormal. Amer. J. clin. Path., 47, 249-268.

Iffy, L. (1963). The time of conception in pathological gesta-tions. Proc. rov. Soc. Med., 56, 1098-1 100.

Janerich, D. T., Piper, J. M., and Glebatis, D. M. (1974).Oral contraceptives and congenital limb-reduction defects.New Engl. J. Med., 291, 697-700.

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Jones, K. L., Smith, D. W., Ulleland, C. N., and Streissguth,A. P. (1973). Pattern of malformation in offspring ofchronic alcoholic mothers. Lancet, 1, 1267-1271.

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Lewis, B. V. (1974). The action of drugs on the uteroplacentalcirculation and the developing fetus. In Obstetric Thera-peutics, edited by D. F. Hawkins, ch. 2, pp. 71-105.Bailliere Tindall, London.

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Stirrat, G. M., and Beard, R. W. (1973). Drugs to be avoidedor given with caution in the second and third trimesters ofpregnancy. Prescribers' J., 13, 135-140.

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