Foetotoxic Effects of CO

shock฀ and฀ post-mortem฀ examination฀ revealed฀ multiple฀ brain฀ malformations฀ [149] .฀ The฀ mother’s฀CO–Hb฀level฀was฀14,฀and฀she฀also฀smoked฀about฀15฀cigarettesday. Sixty฀cases฀of฀CO฀poisoning฀in฀pregnant฀women฀were฀collected฀in฀a฀retrospective฀survey:฀ adequate฀information฀concerning฀the฀severity฀of฀CO฀exposure฀was฀available฀for฀42฀of฀these฀ cases฀Table฀ 8.6 .฀Overall,฀ten฀cases฀of฀CO฀poisoning฀subsequently฀led฀to฀malformations฀in฀ the฀ children฀ absent฀ or฀ malformed฀ extremities,฀ brachycephaly,฀ craniosynostosis,฀ multiple฀ contractures฀of฀the฀extremities,฀hypoplastic฀lungs,฀hydrocephalus,฀ear฀anomalies฀etc.฀ [148,฀ 150–152] ฀and฀a฀high฀proportion฀of฀the฀mothers฀n฀=฀26฀gave฀birth฀to฀stillborn฀infants฀ [150] . Maternal฀CO–Hb฀levels฀are฀particularly฀important฀in฀this฀context.฀One฀prospective฀study฀ conducted฀between฀1985฀and฀1989฀examined฀foetal฀outcomes฀in฀32฀women฀following฀acci- dental฀CO฀poisoning฀due฀to฀a฀variety฀of฀causes.฀The฀sources฀of฀CO฀were฀malfunctioning฀fur- naces,฀hot-water฀heaters,฀car฀exhaust฀fumes฀and฀methylene฀chloride฀inhalation.฀Pregnancy฀ outcome฀was฀adversely฀affected฀in฀3฀out฀of฀5฀pregnancies฀with฀severe฀toxicity:฀two฀stillbirths฀ and฀one฀cerebral฀palsy฀because฀of฀ischaemic฀damage.฀The฀women฀received฀hyperbaric฀oxygen฀ therapy฀immediately฀after฀poisoning,฀with฀the฀result฀that฀31฀neonates฀showed฀normal฀physical฀ development฀despite฀mild฀or฀moderate฀CO฀poisoning฀in฀utero.฀Severe฀maternal฀CO฀toxicity฀ was฀associated฀with฀signiicantly฀more฀adverse฀foetal฀effects฀ [153] .฀In฀a฀further฀six฀women฀ with฀CO฀poisoning,฀there฀were฀two฀abortions฀and฀one฀preterm฀delivery฀with฀numerous฀mor- phological฀anomalies฀ [151] .฀Several฀studies฀indicate฀that฀hyperbaric฀oxygen฀ventilation฀is฀the฀ treatment฀of฀choice฀for฀reversing฀the฀effects฀of฀CO฀toxicity฀ [153,฀154] . In฀women฀with฀pregnancy-induced฀hypertension฀and฀pre-eclampsia,฀endogenous฀CO฀ formation฀is฀somewhat฀lower฀than฀in฀normotensive฀pregnant฀controls฀1.17฀±฀0.35฀vs.฀1.70฀±฀ 0.54฀ppm฀ [153] ,฀with฀CO฀being฀accorded฀a฀contributory฀role฀in฀the฀paradox฀of฀the฀seem- ingly฀protective฀effect฀of฀smoking฀to฀decrease฀the฀risk฀of฀pre-eclampsia฀ [155] .

8.6 Effects of Nicotine on the Foetus

Little฀has฀been฀published฀concerning฀the฀teratogenic฀or฀embryotoxic฀and฀fetotoxic฀effects฀of฀ nicotine.฀Instead฀of฀pure฀nicotine,฀a฀few฀animal฀experiments฀have฀used฀aqueous฀extracts฀of฀ chewing฀tobacco,฀involving฀pre-฀and฀postconceptional฀intragastric฀administration฀of฀doses฀ of฀4,฀12฀and฀20฀mgkg฀body฀weight฀three฀times฀daily฀to฀CD-1฀mice.฀The฀plasma฀nicotine฀ levels฀measured฀30฀min฀after฀administration฀ranged฀from฀99฀to฀623฀ngml.฀This฀overdosing฀ led฀to฀the฀death฀of฀18฀and฀31฀of฀the฀dams฀in฀the฀two฀highest฀dosage฀groups.฀Following฀ Outcome฀for฀the฀foetus Severity฀of฀maternal฀CO฀exposure Minimal Moderate Severe฀death No฀sequelae 4 ฀ 2 – Survived฀with฀malformations฀ andor฀functional฀impairment – 10 – Death – 15 11 Table 8.6 ฀฀฀Maternal฀CO฀poisoning฀and฀implications฀for฀the฀foetus฀or฀child;฀summary฀of฀42฀out฀of฀60฀ cases฀of฀CO฀exposure฀from฀the฀literature฀for฀which฀adequate฀information฀was฀available฀ [150] administration฀of฀the฀highest฀dose,฀the฀foetal฀weights฀of฀the฀mice฀were฀reduced฀by฀7.4,฀and฀ external฀malformations฀were฀few฀and฀only฀minor฀in฀extent.฀Otherwise,฀precocious฀ossiica- tion฀was฀observed฀in฀the฀top฀dosage฀group฀ [156] .฀Only฀minimal฀changes฀were฀noted฀in฀a฀ second฀study฀in฀mice฀following฀administration฀of฀12฀mg฀nicotinekg,฀and฀fatalities฀and฀mal- formations฀were฀not฀detected฀ [157] .฀In฀another฀study,฀pregnant฀rats฀were฀exposed฀to฀ciga- rette฀smoke฀or฀injected฀with฀nicotine฀for฀20฀days.฀Markedly฀reduced฀weight฀gain฀during฀ pregnancy฀was฀detected฀only฀in฀the฀smoke-exposed฀rats฀ [158] .฀Short-term฀administration฀of฀ high฀doses฀of฀nicotine฀in฀animal฀experiments฀adversely฀affects฀the฀maternal฀and฀foetal฀car- diovascular฀system฀whereas฀the฀nicotine฀doses฀used฀in฀pregnant฀humans฀to฀achieve฀smoking฀ cessation฀nicotine฀replacement฀therapy;฀see฀ Chap.฀11 ฀do฀not฀affect฀the฀cardiovascular฀sys- tem฀ [36] .฀In฀particular,฀CO฀and฀Pb 2+ ฀from฀tobacco฀smoke฀have฀been฀cited฀as฀reproductive฀ toxins฀ [36] .฀Breast-feeding฀over฀the฀irst฀4–5฀months฀of฀life฀is฀also฀useful฀for฀reducing฀the฀ risk฀of฀childhood฀asthma฀ [159] . Following฀treatment฀of฀pregnant฀rhesus฀monkeys฀with฀1.5฀mg฀nicotinekgday฀from฀day฀ 26฀to฀day฀160฀of฀gestation,฀the฀absolute฀birth฀weights฀of฀neonatal฀monkeys฀was฀not฀changed,฀ although฀there฀was฀a฀10฀reduction฀in฀birth฀weights฀with฀nicotine฀exposure฀when฀they฀ were฀normalised฀to฀maternal฀weight.฀Plasma฀leptin฀levels฀measured฀on฀postnatal฀day฀1฀ were฀reduced฀by฀50฀in฀the฀nicotine฀treatment฀group,฀relecting฀a฀decrease฀in฀NPY-mRNA฀ expression฀in฀the฀neonatal฀monkeys฀ [160] .฀It฀has฀been฀suggested฀that฀nicotine฀exposure฀ during฀pregnancy฀may฀increase฀energy฀expenditure฀in฀hypothalamic฀structures,฀resulting฀in฀ lower฀birth฀weights฀and฀body฀fat฀levels฀ [160] . Rat฀ pups฀ were฀ exposed฀ to฀ nicotine฀ 6฀ mgkgday฀ under฀ controlled฀ conditions฀ from฀ postnatal฀days฀4฀to฀9,฀using฀a฀procedure฀that฀ensured฀that฀observed฀effects฀are฀not฀due฀to฀ nutritional฀deicits.฀Examination฀of฀the฀animals฀on฀postnatal฀day฀18–19฀revealed฀that฀nico- tine-exposed฀animals฀were฀overactive฀compared฀with฀those฀with฀controls฀ [161] .฀Transposed฀ to฀the฀situation฀in฀humans,฀this฀could฀mean฀that฀maternal฀smoking฀during฀pregnancy฀is฀ associated฀with฀an฀increased฀prevalence฀of฀children฀with฀hyperactivity฀disorder฀ [162] . No฀differences฀in฀3H-nicotine฀binding฀were฀detected฀in฀14฀different฀brainstem฀regions฀in฀ SIDS฀victims฀compared฀with฀healthy฀controls.฀In฀contrast,฀in฀controls฀whose฀mothers฀smoked฀ during฀pregnancy,฀up-regulation฀of฀the฀3H-nicotine฀binding฀sites฀was฀detected฀in฀three฀dif- ferent฀regions฀responsible฀for฀cardiorespiratory฀functions.฀This฀up-regulation฀was฀absent฀in฀ the฀corresponding฀brainstem฀regions฀of฀SIDS฀victims฀ [163] ;฀however,฀this฀inding฀does฀not฀ yet฀permit฀any฀conclusions฀regarding฀the฀pathophysiology฀or฀pathogenesis฀of฀SIDS.

8.7 Smoking and Breast-feeding

A฀study฀was฀conducted฀in฀Norway฀between฀1970฀and฀1991฀to฀investigate฀smoking฀behav- iour฀ during฀ pregnancy฀ in฀ 24,438฀ mothers.฀ During฀ that฀ period,฀ the฀ number฀ of฀ smoking฀ mothers฀fell฀from฀38฀to฀26.฀The฀proportion฀of฀breast-feeding฀non-smokers฀was฀twice฀that฀ of฀breastfeeding฀smokers.฀Where฀only฀the฀father฀smoked,฀mothers฀stopped฀breast-feeding฀ earlier฀than฀where฀the฀father฀was฀a฀non-smoker฀ [164] .฀These฀data฀are฀probably฀also฀repre- sentative฀for฀other฀countries.