Effects of Nicotine on the Foetus

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. Because฀of฀its฀lipophilic฀character,฀nicotine฀passes฀very฀rapidly฀into฀breast฀milk฀where฀it฀ attains฀threefold฀higher฀concentrations฀than฀in฀blood฀ [165,฀166] .฀On฀the฀basis฀of฀the฀volume฀ of฀breast฀milk฀consumed,฀this฀means฀that฀the฀infant฀receives฀6฀µg฀nicotinekg฀body฀weight฀ daily฀ [165] .฀Cotinine฀levels฀are฀an฀indicator฀of฀smoking฀habits฀and฀correlate฀with฀the฀number฀ of฀cigarettes฀smoked฀ [167] .฀The฀infant’s฀urinary฀cotinine฀comes฀from฀the฀cotinine฀in฀the฀ mother’s฀breast฀milk.฀It฀is฀dificult฀to฀assess฀what฀proportion฀derives฀from฀inhalation฀because฀ of฀passive฀exposure฀by฀being฀in฀the฀same฀room฀as฀smokers฀ [168] .฀The฀elimination฀half-life฀ for฀nicotine฀in฀breast฀milk฀is฀somewhat฀higher฀than฀that฀in฀the฀mother’s฀blood฀97฀±฀20฀vs.฀ 81฀±฀9฀min;฀p฀฀0.05,฀whereas฀cotinine฀concentrations฀remain฀fairly฀consistent฀during฀a฀4-h฀ interval฀without฀smoking฀ [166] .฀Newborn฀infants฀breast-fed฀by฀smokers฀and฀unexposed฀to฀pas- sive฀smoking฀show฀low฀plasma฀levels฀of฀nicotine฀0.2–1.6฀ngml฀and฀cotinine฀5–30฀ngml.฀ Newborn฀infants฀breast-fed฀by฀non-smokers฀did฀not฀have฀measurable฀amounts฀of฀the฀two฀ substances฀in฀plasma฀ [169] .฀As฀shown฀by฀the฀data฀presented฀in฀Table฀ 8.7 ,฀breast-feeding฀ mothers฀clearly฀contribute฀to฀raised฀plasma฀nicotine฀levels. Nicotine฀and฀cotinine฀concentrations฀in฀breast฀milk฀increase฀with฀the฀number฀of฀cigarettes฀ smoked฀daily,฀with฀concentrations฀up฀to฀1.6฀ng฀nicotineml฀and฀20฀ng฀cotinineml฀having฀ been฀measured฀ [170] .฀Concentrations฀arising฀as฀a฀result฀of฀passive฀smoking฀are฀markedly฀ lower.฀Nicotine฀and฀cotinine฀levels฀were฀measured฀by฀gas฀chromatography฀in฀34฀human฀milk฀ samples:฀nicotine฀was฀not฀found฀in฀the฀6฀samples฀of฀milk฀from฀non-smokers฀but฀was฀detected฀ in฀the฀28฀samples฀from฀smokers฀average:฀91฀ppb;฀ranging฀from฀20฀to฀512฀ppb฀ [171] .฀The฀ varying฀nicotine฀levels฀did฀not฀cause฀any฀adverse฀effects฀in฀the฀breast-fed฀children฀ [171] .฀ Urinary฀cotinine฀levels฀in฀breast-fed฀infants฀of฀smoking฀mothers฀were฀ten฀times฀higher฀than฀ those฀in฀bottle-fed฀infants฀of฀smoking฀mothers฀ [172] .฀Cotinine฀levels฀were฀also฀increased฀ when฀infants฀of฀non-smoking฀mothers฀lived฀in฀households฀with฀other฀smokers.฀In฀this฀group฀ the฀differences฀compared฀with฀infants฀of฀smoking฀mothers฀were฀very฀minimal฀ [172] ,฀sug- gesting฀that฀passive฀smoking฀must฀be฀recognised฀as฀a฀pivotal฀cause฀of฀the฀accumulation฀of฀ products฀of฀combustion.฀In฀addition,฀Cd 2+ ฀levels฀in฀breast฀milk฀are฀raised฀in฀smokers฀ [27] . Overall,฀breast-feeding฀is฀useful฀because฀the฀risk฀of฀childhood฀wheezing฀is฀reduced,฀even฀ where฀mothers฀smoke฀ [173] .฀It฀is฀still฀better฀–฀but฀far฀from฀ideal฀–฀to฀smoke฀and฀breastfeed฀ than฀to฀smoke฀and฀not฀breastfeed฀ [174,฀175] ,฀although฀it฀is฀known฀that฀smokers฀breastfeed฀for฀ a฀clearly฀shorter฀period฀than฀non-smokers฀ [176] ,฀owing฀possibly฀to฀a฀reduction฀in฀prolactin฀ levels฀ [177] .฀Initial฀investigations฀also฀suggest฀that฀breast-feeding฀for฀5–6฀months฀beneits฀the฀ child’s฀cognitive฀development฀to฀a฀greater฀extent฀than฀breast-feeding฀for฀3฀months฀ [178] . Infant฀exposure฀pattern Nicotinecreatinine฀ratio฀ ng฀nicotinemg฀creatinine Cotininecreatinine฀ratio฀ ng฀cotininemg฀creatinine Newborn฀infants฀breast-fed฀฀ by฀smoking฀mothers฀and฀ unexposed฀to฀passive฀smoking 14฀5.0–110.0 110฀10–550 Non-breast-fed฀infants฀exposed฀ only฀to฀passive฀smoking 35฀4.7–218.0 327฀117–780 Infants฀exposed฀to฀passive฀smoking฀ and฀to฀smoke฀via฀breast฀milk 12฀3.0–42.0 550฀225–870 Table 8.7 ฀฀฀Urinary฀excretion฀of฀nicotine฀and฀cotinine฀in฀breast-fed฀infants฀ [169] Median฀nicotinecreatinine฀and฀cotininecreatinine฀ratios฀and฀ranges