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Drugs in pmgnaney: efffe8zts on postmnatal development and behaviour Susan M. Barlow Llepu~~m~n; o J t’hhsmocolo~.v. Gqv’.s I fosr,ifrd hfdid Srhd, Lwdon SE I WT. L? K. --

Since t~~~~~e, there has &en no diffi culty in persuading physicians that drug intake during pregnancy might cause COB genital malformations. Yet the idea that drugs might also cause more subtle defects. resulting not in gross structural defo~ities but in alterations of post-natal development and behaviour (‘behavioural teratogens’), is still not widely accepted. In terms of human handicap. however. deficits such as mental ~fa~atjon are often far mom devaa tating to the individual and the family rhan a structural maiforfnation, like cleft palate for example. which may be successfully cor- rected surgically. Furfhennore, since many im~ant aspects of brain devel~~nt, such as cell proliferarion, miprdtion and dif- fercntiafion. synaptogenesis. and myelin. ization. occur late in gestation and post- natally. then if is also important to revise the w~ely-old notion that the developing embryo is only vulnerable to insult during critical periods of organogenesis in early pregnancy.

Experimental evidence for the existence of behavioural feratogens in now consider- able (Table I). In humans. there is evidence that prenatal exposure to opiates, alcohol, ant~con~l~nts such as phenytoin and trimethadione. and the environmental con. frminam. methylmercury, can affect post.

natal developfnenf and ~haviour in chil- dren whose structural appearance is not par- Gcularly remarkable. That is not to say that such functional deficits do not have any underlying structural or biochemical path~ogical correlates. but rather that such changes nray only be apparent in detailed post-mortem examination and only if the investigator knows where to look.

Experimental behavioural teratology is currently pursuing two major avenues. first, the development of reliable teehni- ques suitable for screening of compounds both new and old for possible post-natal effects and, secondly, conelation of observed ~n~tional deficits with specific alterations in theCNS. Bothare designed to enhance the predictive value of experimcn. fal behavioural reratology in relation to human prenatal drug exposure and may also further knowledge about nofmal bmin development by the use of behaviourai ferafogens as investigative tools.

One of the earliest experimental observa. tionsof a behavioural feratogenic effect was pubiis~d by Harned ad co-workers in 1940, showing impaired mazelearning ability in rats born to dams treated during pregnancy with the then widely used trae quill&r, sodium bromide’. However. the term ‘~havi~ra) ferafofogy’ was fit used in l%3=, foitowing a series of experiments by We&off and his colleagues, in which rats exposed prenatally to psychotropic drugs, such as chlorpro~r:atine, meprobs mate, resefpine. iproni~id and S- hydroxytryptophan. were found to differ post-natally from controls in a number of ways. These included increased neonatal mortality. post-natal growth retardation, altered locomotor activity and ‘emotional reactivity’, altered susceptibilty to audiogenic seizures and maze-learning deficits. the precise behavioural profile depending on the drug used. Thus. the term ~~v~uml teratol~y , defined by We&off and Gottiieb as the effect of prenatal expos. ufe todrugs on the ‘behaviour, or functional adaptation of the offspring (0 its envirorr merit’*,, is to sofne extent a misffofner, since it now encompasses many aspeets of post-

natal ~velc~pfnenf in relation to prenatal or p&fatal dmg exposure, in a comprehen- sivc screen, growth. phystcal development, functional development of reflexes. vision. audifion. olfaction and locomotion may be stud&l, as well as aspects which might be regarded as ‘behaviour’ in its true sense, such as learning ability. cxpforatofy acfiv- ify, social interaction in groups. etc. It may even include less obvious areas such as alt erations in ~mafological ~ranieters, car- diovascuiar function. reproduclivccapacity and immune fun&n. Since noi all of these necessarily involve disturbances in CNS function. post-natal evaluation of prenatal drug exposure might more properly bc described as developmental toxicology.

Psychotropic agents The majorit, .*f studies in this area have

employed psychotropic drugs since it has been surmised that drugs which have a transient pharmacological effect on the adult brain nfighf produce more persistent changes in the developing brain. Reserpine for example. one of the first behaviourat teratoge discovered, has been shown to interfere ,vith cell proliferation in the brain; s.c. injection of resefpine into neonatal rats reduces p~iferation in the cerebeiiar external granular layer (by prolongation of the cell cycle time) and in the forebrain subependymal layer (by increasing cell death) and thereby may nesuft in a permanent deticit”.

It has been suggested that since some transmitters are synthesized and stored :n monoaminergic ceils early in brain development, before most other neuronal ceil types including their ultimate target cells are fully formed, they may have an additional function to regulate the growth and differentiation of nerve cells. If indeed neurotransmitters such as noradrenaline do control cell p~life~tion in the developing brain, then agents which act as monoamine agonists or antagonists may disturb normal patterns of ceil proliferation sufftcienfly to cause functional deficits or persistent obvious changes.

I1P.V - Jwt~ I ‘W

.Agcn~\ which have lr;micru clkc~s 1~1

IiC’ur(llriliihllllh~l~ln w PJUIIS mlghr ;II\o ha\c

more pcr~lslcnl cffcc@ on Ilrur(rlrilll~nlilllr~

in lhc dcwlq%g hr..m Expwlrc !>1’ nc(b

nalcs vlil Ihc nl:llerna~ milk lo &up bnwn IO

block ccnlral calccholammr receptor\ in

;~dult~ ha\ hccn shown 11) mterfcrc UIIII

niolw dcvclopmcnl Wld Icarninp ahilil! in

young animals”. In thr rat. and pruhabl~

Au lhc rahhrt. dopaminergic ~yuroncs

develop lhcir function\ port-nalally durmg

Ihc first ~4. of lift. In the rahhu. Irex.

nlenl (II’ nursing molhcrh with h;lloprM

for rhe lint 7 days of IacWon ha\ no eftcct

on the mothers hul the ofl\pring \hllM

delayed developmcnl of Ihc righting rellrx.

normally prcscnt al X-14 da)> <)I agr. and

an ahnormal fait ailh lhGr!cnl hind limb

dysfunction still prcscnt at 4 sock\ of ags.

In the rat. Irc’atmcnr ot~nur~ing mclthrrs ior

the first 7 J:I~s of lactation rrith pcnllumlcrl

or pimoridr. thought IO prclcrcnua~l) hloch

dopamine receptors. impair\ .IcqmWlon 411

a conditioned avoidance re\pon\c in the

oH’~pring at 1 \ceeks of age and aherr

l~omolcx aclivily up to at least 12 week% of

age. Biochemical analysis of the hrainb 01

-L\ccch-old pentluridol-lrcated rats pm-

duced evidence of decreased dopamine

\jnthesis and decreased impulse actrvir! in

the normally dopamine-rich part of Ihe

limhic system. Thus. we might predict that

other psychotropic drugs blocking neuro.

lransmilter release or rcceplor interactions

would he lxhavioural teratogens if given at

the appropriate time.

Cytotoxic agents Another proup of drugs that might be

expected to be behavioural teratogens xe

rhe cytotoxic agents such as hydroxlurea

and S-azacytidine. which selectively inter-

fere with DNA synthesis or with mitosis.

By manipulalinp the time (1’ which such

drugs are administered it ha!. heen possible

to produce selective reductians in specific

cell popuMons in rhe CNS. reaulling in

piU?icUlar lypes of motor deficit or

behavioural change, depending on whrch

blructurcs arc: dumaged”. In swne c’aa.

hchaviclural rifects have hccn ShoB n after

Iobso1’a~ lialr ah!& of the lolai cell popula-

tion in one arca. In the developing CNS. the day a 4

undergoes iI\ final division is known as i!s

‘hirWay‘. By laiwlling cells with trilialed

thymidinc just prior lo their final division it

is pussihle IU hkr identify the tinx oforipin

oC neurons in different arcas of Ihe bruin;

the culls with the heaviest lubelling are

those u’hich underwent final division jusl

after the time ofadrninistraWt of the label.

In this way. a picture has been built up in

Ihc rodent brain showing the differing limes

of origin oC neuron!. in dit’krent areas”. For

256

The same group of workers who idet+ t&d the fetal alcohol SyndtVme were also first to describe a cluster of anomalies in children exposed fatally to hydantoin anti-convulsants. such as phenytoin. which they designated the ‘C’al hydantoin syn- drome“. The syndmtw is characterized by specitic craniofacial anomalies, hypoplasia of the digits, with growth, ~v~op~tai and mental retardation. As in the fetal alcohol syndrome, the structural defects ate mild and it is lhe functional and intel@ctuai impairments which .im of greatest concent. At 2 yearsof age. signi~~nt im~i~m of gross and fine motor co-ordination and poor language acquisition have been fwnd, while in children invesoigated at 7 years of age JQ scores were lower than matched COW t&s. 1Q def%its have not been found in offspring of epileptir: wamen taking phenobarbitone. which strongly points IO phenytoin rather than !he epilepsy itself as the behavioural teratogen.

Narcotics such as herSn and methadone have also been implicated as behavioural teratogensa’U. Besides ~suducing a charac- teristic withdrawal syndrome in neonates born to narcotics addicts. there is some evi dence in the children of disturbed sleep pat- terns and hyperactivity up to 2 years of age and more persistent problems causing dif- ticuhiis in sshool work, suchas short atten- tion spans. However. there are olher con. founding variables such as abuse of other drugs and poor nutrition during pregnancy. maternal smoking and drug treatment of rhe neonatal wiU&awal symptoms, which are CScuit to disentangle from thr. possible effects of the opiates themsetves.

Similarly, a number of studies have shown that anaesthetic and analgesic drugs usedduring fabour are associated with mod. &cations in infant behaviottr, but many have methodological shortcomings which prevent precise delineation of the nature and extent of the changes at thi:i point in time‘s**. Et&cc have been noted in the fmt month of life on infan; suckhtg behaviour, mother-infant inieractions. irritability. habituation, orientiw responses am-t akWtess. whilst in large. lon~te~ fotiLw-np studies to 7 years of age, delays in motor development, language develop nbmt and acquisition of cqnitive skills have been fotmd. In view of the prevalence of obstetric lotion, this area clearly warrants further study.

Then? can now bz Wle doubt that some drugs have the potential to interfern with brain development in such a way as Ito po. duce tiut&o& and behaviotuai defEits in the absence Of gross strucmral deformities. The appearance of hebaviouml disorders in

children may be months or even years removed fmm the ~~ipi~ting prenatal events, so discovery of behavioural teratogens is unlikely from casual observe. don. except where cases may be clustered, as in prenatal methylmercury poisoning and cerebral palsy in Japan, or whete there may be an additional marker such as facial dyrc ~~ogy seen in the fetal alcohol and hydantoin syndromes. However, evidence to date suggests that for methyhnercury, alcohol and phenytoin. effects in animals are very similar to those observed in humans. Thus, we may hope that carefully conthllled animal studies may be of useful predictive value for evahratiim of the post- natal effects of drugs used in pregnancy.

Reading I&t I Hamed, B. K.. Hemiib\n. H. C. and Bnrmr. J) C.

(lyJO)Am. /. Med. Sci. HIO. &I6 2 Werhoff, J amJ Gottlicb, J. S. (1%3) Uhsfe?.

r;vnu,or. smv. l8.426423 3 Lewis. P. 0.. Pdlel. A. I., B&&k. 0, and Balhzs.

R. (l~771fk~er i. 399401 4 Lundhnrg, P. nnd Engel, 1. (19771 inAdwnrrs in

the Dtw&n of Congenifof Mulfona~ions (van ~~~~~. E. B., Tesh. J. M. SKI Fam, G. M.. ois), pp. w-106. Eutapemt Tcnmlwy Swiety. lark. Esnr

bdvances in renal pharmacology:

Mroduct&n Tbe general topics of renal $3rmacol-

ogy and toxi~logy have become extremety diverse. Both the quantity of material avail- able as well as its variety preclude a thorough review of these topics. For exam pie, the whole area of renal prostaglandins and other intrarenal hormones wonld corn-- prise a topic for review entirely by Bself, e.g. .see Annual Review of Ptttmwcoi- ogy and To.rico~ogy , I98 I.

In general, the xenobiotics that alter renal fun&on are comprised of chemicals that produce both desirable or undesirable effects. Some brief eomments on the diure tics, especially the more modern, useful ones will represent an examination of desir- able renobiotics’. U~s~b~ effects ate alsopmduced by drugs, but most often such efftits a thought of as egging to the reala~ OA &ions caused by environmental coWuninants. Renal toxicology, therefore,

whether involving undesirable effects of drugs or actions produced by environmen- tal cont~inants, is pmving to be a most active and fruitful research area at the pree ent time. Hence, a brief discussion of some aspects of renal toxicology also will be included in this perspective.

Renal pharmac&rgy from the mid- 1950s Diuretic therapy has been in and out of

vogue throughou\ medical history. Perhaps the most dramatic effects in modem diure- tic therapy in the U.S.A. were related to the introduction of the organomercurial diure- tics in the 192Cts. These substances served as the maimtay ofdiuretic therapy for many years, indeed, extending into the I96Os. Wipite the acceptance ~f~gan~~urials as effective therapeutic agents, it was long t~~gnized that thy possessed a variety of disadvantages ranging from the htconven. ience involved in their administration to