Malformations Possibly Caused by Smoking

a฀chance฀event฀ [86] .฀The฀development฀of฀neural฀tube฀defects฀is฀a฀controversial฀topic฀ [97,฀98] ฀ but฀the฀association฀with฀maternal฀smoking฀during฀pregnancy฀is฀less฀likely. The฀risk฀of฀oral฀clefts฀cleft฀lip฀and฀palate฀has฀been฀considered฀repeatedly฀in฀the฀con- text฀of฀maternal฀smoking฀Table฀ 8.5 ฀ [97,฀99] .฀Studies฀rejecting฀such฀an฀association฀have฀ occasionally฀appeared:฀for฀example,฀one฀recently฀published฀study฀has฀reported฀higher฀odds฀ ratios฀1.09–1.85฀for฀oral฀clefts฀with฀increasing฀cigarette฀consumption,฀but฀no฀associations฀ were฀identiied฀between฀clefting฀type฀and฀smoking฀habits฀ [100] . The฀association฀between฀maternal฀smoking฀during฀pregnancy฀and฀the฀development฀of฀ cleft฀lip฀and฀palate฀in฀infants฀has฀been฀demonstrated฀elsewhere฀ [97,฀99] .฀One฀case฀-control฀ study฀conducted฀in฀Maryland฀between฀1992฀and฀1996฀revealed฀no฀statistically฀signiicant฀ association฀between฀maternal฀smoking฀and฀oral฀cleft฀development,฀although฀there฀was฀a฀ slight฀increase฀in฀the฀C2฀allele฀on฀the฀TGFa฀genotype฀among฀cases฀of฀oral฀cleft฀ [46] .฀In฀con- trast,฀another฀US฀study฀showed฀increased฀risks฀for฀isolated฀cleft฀lip฀OR฀=฀2.1฀and฀for฀iso- lated฀ cleft฀ palate฀ OR฀ =฀ 2.2฀ when฀ the฀ mothers฀ smoked฀ 20฀ or฀ more฀ cigarettesday.฀ This฀ corresponds฀to฀a฀3-฀to฀11-fold฀risk฀increase฀compared฀with฀non-smokers฀ [101] .฀In฀a฀study฀ Malformations Study฀population฀n Risk฀or฀odds฀ratio฀OR References Malformations 86,000฀and฀288,067฀ live฀births No฀association฀with฀smoking฀ OR฀0.98 [44,฀45] Cleft฀palatecleft฀lip 3-and฀11-fold฀increased฀risk [46,฀47] Microcephalus,฀cleft฀ defects,฀clubfoot 3,284฀live฀births฀+฀ 4,500฀controls Association฀conirmed [48] Cleft฀lippalate 6.16-fold฀and฀8.69-fold฀risk฀ increase฀in฀smokers [49] Cleft฀lippalate 1,002,742฀live฀births OR฀1.16฀cleft฀lip,฀1.29฀ cleft฀palate [50] Cleft฀lippalate Meta-analysis฀ 1966–1996 OR฀1.29฀cleft฀lip฀+฀palate฀ and฀1.32฀cleft฀palate [51] Atrial฀septal฀defects No฀association฀with฀smoking [52] Down฀syndrome 1,117,021฀live฀births No฀association฀in฀multiparous฀ women,฀but฀cannot฀be฀ ruled฀out฀in฀primiparous฀ women [53] Limb฀defects฀and฀limb฀ reduction฀defects 1,575,904฀and฀ 1,109,299฀live฀ births฀610฀infants OR฀1.26–1.70 [54–56] Urinary฀tract฀ malformations฀and฀ polycystic฀kidneys 118฀live฀births฀+฀369฀ controls,฀and฀ 1,117,021฀live฀ births OR฀2.3฀and฀1.22฀respectively [57,฀58] Aortopulmonary฀ septal฀defects OR฀1.9 [56] Craniosynostosis Increased฀risk฀with฀higher฀ antenatal฀maternal฀ altitude [59,฀60] Gastroschisis Children฀born฀to฀ mothers฀below฀25฀ years฀of฀age OR฀2.0 [61] Table 8.5 ฀฀฀Malformations฀possibly฀caused฀by฀cigarette฀smoking conducted฀in฀almost฀3.9฀million฀live฀births฀in฀the฀USA,฀2,207฀live฀births฀with฀cleft฀lippalate฀ were฀identiied฀ [102] .฀A฀signiicant฀association฀was฀found฀between฀any฀amount฀of฀maternal฀ cigarette฀ use฀ during฀ pregnancy฀ and฀ having฀ a฀ child฀ with฀ a฀ cleft฀ lippalate฀ OR฀ =฀ 1.55.฀ Additional฀factors฀such฀as฀maternal฀education฀level,฀age,฀race฀and฀maternal฀medical฀condi- tions฀e.g.฀diabetes฀or฀pregnancy-associated฀hypertension฀were฀potential฀confounders.฀After฀ adjusting฀for฀these฀confounders,฀a฀dose-response฀association฀with฀smoking฀was฀shown,฀by฀ comparison฀with฀the฀non-smoking฀reference฀group:฀the฀odds฀ratios฀were฀1.50฀1–10฀ciga- rettesday,฀1.55฀11–20฀cigarettesday฀and฀1.78฀20฀cigarettesday฀ [102] .฀Infants฀carrying฀ the฀rarer฀C2฀allele฀at฀the฀TaqI฀site฀in฀the฀TGFa฀locus฀who฀were฀exposed฀to฀maternal฀smoking฀ were฀more฀likely฀to฀develop฀cleft฀palate฀6.16-fold฀risk฀increase฀at฀10฀or฀fewer฀cigarettesday,฀ 8.69-fold฀risk฀increase฀at฀more฀than฀10฀cigarettesday฀ [49,฀103] . TGFa,฀TGFb3,฀RARA฀retinolic฀acid฀receptor฀and฀the฀proto-oncogene฀BCL-3฀have฀ been฀found฀to฀be฀useful฀markers,฀although฀allocation฀of฀the฀various฀clefting฀types฀to฀the฀ described฀genes,฀TGFa,฀TGFb3฀and฀MSX1,฀is฀possibly฀premature฀ [104] ,฀as฀is฀conjec- ture฀whether฀multivitamin฀juice฀consumption฀during฀pregnancy฀interferes฀with฀the฀TGFa฀ gene฀ [105] .฀An฀association฀between฀smoking฀and฀the฀occurrence฀of฀this฀anomaly฀has฀not฀ been฀demonstrated. Further฀ malformations฀ were฀ identiied฀ in฀ a฀ study฀ conducted฀ in฀ four฀ Polish฀ districts:฀ these฀occurred฀in฀between฀1.1฀and฀1.9฀of฀neonates฀and฀manifested฀themselves฀principally฀ as฀limb฀reduction฀defects฀and฀functional฀disturbances฀of฀striated฀muscle฀ [106–108] .฀An฀ association฀with฀smoking฀was฀less฀likely฀than฀with฀harmful฀environmental฀factors.฀It฀is฀ also฀debatable฀whether฀neural฀tube฀defects฀are฀more฀likely฀to฀develop฀during฀pregnancy฀ when฀the฀mother฀smokes฀ [109] .฀Serious฀defects฀that฀have฀also฀been฀linked฀with฀smoking฀ include฀changes฀consistent฀with฀holoprosencephaly,฀a฀condition฀characterised฀by฀abnormal฀ forebrain฀and฀midfacial฀development฀and฀by฀failure฀of฀cleavage฀into฀left฀and฀right฀hemi- spheres.฀ Compared฀ with฀ controls,฀ maternal฀ periconceptional฀ exposures฀ associated฀ with฀ increased฀risks฀for฀holoprosencephaly฀included฀cigarette฀smoking฀OR฀=฀4.1,฀and฀com- bined฀alcohol฀and฀smoking฀OR฀=฀5.4,฀and฀these฀increased฀risk฀levels฀were฀only฀surpassed฀ by฀women฀with฀insulin-dependent฀diabetes฀OR฀=฀10.2฀ [110] . Mothers฀who฀smoke฀during฀pregnancy฀are฀more฀likely฀to฀have฀offspring฀with฀congeni- tal฀urinary฀tract฀anomalies฀OR฀=฀2.3.฀This฀risk฀was฀higher฀OR฀=฀3.7฀among฀light฀smok- ers฀1–1,000฀cigarettes฀during฀the฀pregnancy฀than฀among฀heavy฀smokers฀OR฀=฀1.4฀ [57] .฀ Polycystic฀renal฀changes฀have฀been฀reported฀most฀commonly฀ [58] . Child฀behaviour฀has฀also฀been฀studied฀in฀terms฀of฀maternal฀smoking฀during฀pregnancy:฀ where฀ the฀ mothers฀ were฀ smokers,฀ externalising฀ behaviour฀ problems฀ aggressive,฀ ฀oppositional,฀overactive฀were฀more฀prominent฀in฀the฀children฀than฀internalising฀behaviour฀ problems฀depressed,฀anxious,฀withdrawn,฀and฀the฀effect฀of฀maternal฀smoking฀was฀almost฀ identical฀for฀boys฀and฀girls฀ [111] .฀According฀to฀analyses฀of฀lead฀levels฀in฀the฀blood,฀the฀irst฀ behavioural฀problems฀in฀children฀of฀smokers฀coincide฀with฀raised฀lead฀levels฀ [6] .฀Smoking฀ 10฀or฀more฀cigarettesday฀during฀pregnancy฀doubles฀the฀risk฀OR฀=฀2.0฀of฀infants฀being฀ non-babblers฀at฀the฀examination฀at฀8฀months฀ [112] .฀The฀child’s฀cognitive฀development฀is฀ not฀affected฀by฀maternal฀smoking฀behaviour;฀in฀this฀context,฀social฀background฀and฀life- style฀are฀more฀important฀determinants฀see฀also฀Sect.฀7.1.4฀in฀ Chap.฀7 ,฀ [113] .฀According฀ to฀other฀estimates,฀prenatal฀exposure฀of฀the฀foetus฀to฀nicotine฀may฀lead฀to฀behavioural฀ disturbances฀and฀can฀indicate฀higher฀risk฀for฀psychiatric฀problems,฀including฀substance฀ abuse฀ [114] .฀One฀French฀study฀suggests฀that฀being฀born฀small฀for฀gestational฀age฀at฀full฀ term฀is฀associated฀with฀poorer฀school฀performance฀at฀12฀and฀18฀years฀and฀later฀entry฀into฀ secondary฀school฀than฀children฀born฀appropriate฀for฀gestational฀age฀OR฀=฀2.3฀ [115] .

8.4 Smoking and Sudden Infant Death Syndrome SIDS

An฀ association฀ between฀ smoking฀ and฀ sudden฀ infant฀ death฀ syndrome฀ SIDS฀ has฀ been฀ reported฀in฀several฀publications฀Table฀ 8.4 .฀It฀has฀been฀suggested฀that฀hypoxia฀and฀raised฀ CO฀levels฀in฀foetal฀blood฀during฀pregnancy฀play฀a฀crucial฀role฀in฀the฀context฀of฀SIDS.฀ These฀two฀factors฀exert฀a฀noxious฀effect฀on฀the฀respiratory฀control฀mechanisms฀in฀the฀foe- tal฀brain฀which฀then฀remains฀susceptible฀to฀further฀insults฀in฀the฀early฀post-natal฀period฀ from฀ infection฀ and฀ hyperthermia,฀ resulting฀ in฀ death฀ from฀ central฀ respiratory฀ dysfunc- tion฀ [116] .฀Infants฀born฀to฀smoking฀mothers฀have฀a฀reduced฀drive฀to฀breathe฀and฀a฀blunted฀ ventilatory฀response฀to฀hypoxia,฀possibly฀contributing฀to฀SIDS฀ [117] . According฀to฀investigations฀carried฀out฀in฀piglets,฀infusions฀of฀nicotine฀5฀µgkg,฀IL-1b฀ 10-pmolekg฀and฀nicotine฀plus฀IL-1b฀cause฀prolonged฀periods฀of฀apnoea฀without฀a฀sub- sequent฀hyperventilatory฀response,฀with฀the฀result฀that฀the฀O 2 ฀pressure฀falls฀and฀CO 2 ฀pres- sure฀rises.฀IL-1b฀has฀a฀powerful฀depressant฀effect฀on฀respiration;฀in฀the฀case฀of฀nicotine,฀it฀ has฀not฀been฀clariied฀whether฀the฀plasma฀levels฀achieved฀correspond฀to฀those฀in฀the฀foetus฀ or฀infant฀ [118] . Protein฀kinase฀C฀and฀nitric฀oxide฀synthase฀activities฀in฀the฀dorsocaudal฀brainstem฀of฀rats฀ exposed฀to฀cigarette฀smoke฀from฀day฀2฀to฀22฀of฀pregnancy฀are฀also฀clearly฀reduced฀ [119] ;฀ these฀indings฀possibly฀explain฀the฀decreased฀respiratory฀drive฀and฀enhanced฀hypoxic฀vul- nerability฀ seen฀ in฀ infants฀ born฀ to฀ smoking฀ mothers.฀ According฀ to฀ more฀ recent฀ studies,฀ prenatal฀nicotine฀exposure฀reduces฀vigilance฀altered฀sleep–wake฀rhythm฀by฀increasing฀ the฀expression฀of฀nAChRs฀in฀the฀brain฀regions฀responsible฀for฀regulating฀these฀processes,฀ possibly฀predisposing฀to฀SIDS฀ [120] . In฀a฀case-control฀study฀from฀Sweden฀ [80] ฀comparing฀244฀SIDS฀cases฀with฀869฀controls,฀ maternal฀smoking฀was฀reported฀to฀be฀associated฀with฀a฀4-fold฀increased฀risk฀for฀SIDS.฀It฀is฀ now฀known฀that฀over฀a฀period฀of฀25฀years฀since฀the฀early฀1970s฀there฀has฀been฀a฀rise฀in฀the฀ incidence฀of฀SIDS฀in฀Sweden฀for฀which฀no฀conclusive฀explanation฀can฀be฀found฀ [121] .฀It฀ has฀ been฀ reported฀ that฀ 29฀ of฀ mothers฀ whose฀ infants฀ die฀ of฀ SIDS฀ are฀ smokers฀ [122] .฀ Histological฀examination฀has฀revealed฀increases฀in฀the฀inner฀and฀epithelial฀wall฀areas฀of฀ the฀airways฀in฀infants฀whose฀mothers฀were฀smokers,฀a฀inding฀that฀may฀also฀be฀associated฀ with฀SIDS฀ [123] .฀Research฀conducted฀in฀Shanghai฀in฀2,227฀children฀ [124] ฀to฀investigate฀ the฀synergistic฀effect฀of฀passive฀smoking฀and฀artiicial฀feeding฀detected฀a฀dose-dependent฀ increased฀risk฀of฀hospitalisation฀for฀respiratory฀illnesses฀during฀the฀irst฀18฀months฀of฀life:฀ this฀was฀shown฀separately฀for฀boys฀and฀girls,฀low฀and฀normal฀birth฀weight,฀and฀for฀breast- fed฀and฀artiicially-fed฀infants฀Fig.฀ 8.2 .฀Similarly,฀in฀a฀US฀case-control฀study,฀a฀dose- dependent฀increased฀risk฀for฀SIDS฀was฀reported฀as฀a฀function฀of฀the฀number฀of฀smokers฀ living฀in฀the฀household฀and฀the฀number฀of฀cigarettes฀smoked฀daily฀Fig.฀ 8.2 ฀ [125] . Increased฀ risk฀ has฀ been฀ conirmed฀ in฀ another฀ study฀ [126] ฀ and฀ a฀ secondary฀ role฀ has฀ been฀assigned฀to฀alcohol฀consumption฀ [127] .฀Where฀mothers฀reduced฀or฀ceased฀cigarette฀ consumption฀during฀pregnancy,฀the฀risk฀of฀SIDS฀was฀reduced.฀Causal฀differences฀have฀ been฀ reported,฀ depending฀ on฀ age฀ at฀ death฀ before฀ or฀ after฀ 120฀ days฀ [128] .฀ Late฀ SIDS฀ occurred฀predominantly฀in฀winter,฀and฀a฀variety฀of฀risk฀conditions฀low฀parental฀social฀and฀ educational฀level,฀smoking฀status,฀and฀the฀prone฀sleeping฀position฀were฀important฀in฀both฀ early฀and฀late฀SIDS.฀The฀risk฀of฀SIDS฀was฀increased฀8.4-fold฀in฀preterm฀babies,฀3.4-fold฀in฀ low-birth-weight฀babies฀2,500฀g฀and฀2.2-fold฀when฀the฀mothers฀smoked฀during฀preg- nancy฀ [129,฀130] .฀These฀factors฀underline฀a฀multiple-cause฀hypothesis฀for฀SIDS฀ [126] .฀The฀ SIDS฀rate฀was฀reduced฀when฀infants฀were฀changed฀to฀sleeping฀on฀their฀backs฀ [131] .฀Apart฀ from฀smoking,฀numerous฀other฀sociocultural฀factors฀young฀maternal฀age,฀low฀educational฀ level฀of฀mother฀and฀father,฀frequent฀pregnancies฀etc.฀increase฀the฀risk฀for฀SIDS,฀as฀dem- onstrated฀by฀a฀study฀recently฀conducted฀in฀Norway฀ [132] .฀In฀further฀studies,฀the฀infants’฀ risk฀ level฀ for฀ SIDS฀ was฀ reported฀ to฀ be฀ increased฀ 6.2-fold฀ [133] ฀ and฀ 5.01-fold฀ [127] .฀ According฀to฀the฀Westphalia฀study,฀the฀SIDS฀risk฀increased฀dose-dependently฀from฀2.4- fold฀ in฀ moderate฀ smokers฀ 10฀ cigarettesday฀ to฀ 7.2-fold฀ in฀ heavy฀ smokers20฀ ciga- rettesday฀ [70] .฀ Only฀ preterm฀ babies฀ had฀ an฀ even฀ higher฀ risk฀ 16-fold฀ increase.฀ Very฀ similar฀risk฀assessments฀have฀also฀been฀published฀by฀researchers฀in฀the฀USA฀ [134] ฀and฀ Scotland฀ [135] .฀A฀plasma฀cotinine฀level฀30฀ngml฀has฀been฀recorded฀in฀about฀25฀of฀ SIDS฀children฀ [124] ,฀evidence฀that฀tobacco฀smoke฀and฀hence฀the฀inhaled฀nicotine฀is฀trans- ferred฀to฀the฀foetus. LBW฀is฀an฀important฀risk฀factor,฀given฀the฀proven฀ethnic฀differences฀in฀the฀subsequent฀ occurrence฀of฀SIDS.฀An฀association฀between฀infant฀LBW฀and฀SIDS฀has฀been฀reported฀ among฀whites฀and฀American฀Indians,฀and฀to฀a฀lesser฀extent฀among฀blacks,฀but฀not฀among฀ Asians฀or฀Hispanics฀ [136] . Investigations฀have฀recently฀been฀conducted฀into฀the฀ine฀tissue฀changes฀in฀the฀brain- stem฀of฀SIDS฀victims฀ [137] .฀It฀was฀found฀that฀in฀SIDS฀victims฀there฀was฀41฀probability฀ that฀the฀more฀the฀mothers฀smoked฀during฀pregnancy,฀the฀more฀gliosis฀in฀the฀nucleus฀oliva- ris฀inferior฀was฀found฀in฀their฀infants฀p฀฀0.01.฀Similarly,฀associations฀were฀found฀between฀ gliosis฀in฀the฀nucleus฀olivaris฀inferior฀and฀hypoxic-ischaemic฀events฀during฀pregnancy,฀ birth฀and฀the฀perinatal฀period฀ [137] . Children฀of฀women฀suffering฀from฀schizophrenia฀are฀at฀increased฀risk฀for฀SIDS฀RR฀=฀2.76;฀ CI:฀1.67–4.56฀and฀for฀congenital฀malformations฀among฀their฀children฀RR฀=฀1.70;฀CI:฀ 100 10 1 3 1 2 3 5.3 5.1 2.4 3.6 22.7 20 11−20 1−10 Total Daily Cigarette Exposure Number of Household Smokers Odds Ratio Adjusted ORs for Nonsmokers = 1.0 Fig. 8.2 ฀฀฀Results฀of฀a฀SIDS฀case-control฀study฀from฀the฀USA.฀Smokers฀in฀the฀household฀included฀ the฀children’s฀parents฀and฀other฀live฀in฀adults฀ [125]