Effects of Smoking on the Placenta

hexachlorobenzene฀HCB฀than฀that฀of฀neonates฀born฀to฀passive-smoking฀mothers฀or฀to฀ mothers฀who฀have฀had฀no฀contact฀whatsoever฀with฀tobacco฀smoke฀ [7] .฀Diaplacentar฀trans- mission฀of฀toxic฀substances฀therefore฀plays฀a฀major฀role฀and฀the฀rate฀of฀adverse฀pregnancy฀ outcomes฀in฀women฀who฀smoke฀may฀be฀as฀high฀as฀33฀ [8–11] .฀Syncytial฀necrosis฀and฀ thickening฀of฀the฀trophoblast฀membrane฀have฀been฀detected฀during฀the฀irst฀weeks฀of฀preg- nancy฀in฀the฀placenta฀of฀women฀who฀smoke฀ [12] .฀During฀this฀period,฀stem฀cells฀for฀the฀ formation฀of฀the฀syncytium฀or฀of฀cell฀groups฀fuse฀together฀and฀these฀become฀implanted฀in฀ the฀uterus.฀According฀to฀experimental฀animal฀research,฀smoking฀interferes฀with฀these฀pro- cesses.฀Levels฀of฀the฀marker฀hormones,฀oestriol,฀oestradiol,฀human฀chorionic฀gonadotro- phin฀hCG฀and฀placental฀lactogen,฀are฀reduced฀in฀smokers฀ [13–15] .฀Similarly,฀the฀activity฀ of฀placental฀aromatase฀is฀diminished฀by฀smoking฀ [16] .฀Comparative฀investigations฀of฀pla- cental฀tissue฀from฀smoking฀and฀non-smoking฀women฀smoking฀status฀quantiied฀objec- tively฀by฀the฀measurements฀of฀tissue฀cotinine฀levels฀have฀revealed฀raised฀haematocrits฀and฀ cadmium฀levels฀in฀the฀placental฀blood฀of฀smokers฀ [17] .฀Furthermore,฀the฀relative฀surface฀ areas฀of฀foetal฀capillaries฀as฀well฀as฀the฀relative฀and฀absolute฀volumes฀of฀foetal฀capillaries฀ are฀reduced,฀primarily฀as฀a฀result฀of฀a฀decrease฀in฀mean฀capillary฀diameter฀rather฀than฀total฀ capillary฀length฀ [17] .฀Although฀haematocrits฀are฀increased,฀foetuses฀of฀smoking฀mothers฀ suffer฀hypoxic฀stress;฀overall,฀it฀must฀be฀assumed฀that฀this฀is฀an฀all-or-none฀effect฀rather฀ than฀one฀which฀is฀dose-dependent฀i.e.฀on฀the฀number฀of฀cigarettes฀smoked฀ [17] .฀In฀the฀ irst฀ trimester,฀ the฀ placental฀ volume฀ of฀ smokers฀ is฀ already฀ smaller฀ than฀ that฀ of฀ non-฀ smokersbecause฀ of฀ resistance฀ of฀ high-perfusion.฀ This฀ state฀ also฀ persists฀ in฀ the฀ second฀ ฀trimester,฀with฀the฀result฀that฀3-dimensional฀ultrasound฀can฀be฀used฀to฀draw฀conclusions฀con- cerning฀smoking-related฀impairment฀of฀trophoblast฀invasion฀ [18] .฀Women฀who฀smoke฀during฀ pregnancy฀have฀a฀2.6-฀to฀4.4-fold฀higher฀risk฀of฀placenta฀praevia฀than฀non-smokers฀ [19] . Several฀isoenzyms฀of฀the฀cytochrom฀oxygenase฀system฀occur฀not฀only฀in฀the฀liver,฀but฀ also฀in฀several฀tissues฀such฀as฀the฀placenta.฀The฀activity฀of฀the฀monooxygenase฀system฀ CYP1A1฀increases฀up฀to฀100-fold฀and฀more฀if฀the฀pregnant฀mother฀is฀a฀smoker.฀This฀ enzyme฀is฀induced฀by฀polyaromatic฀compounds,฀but฀not฀by฀phenobarbitone฀ [20–25] .฀It฀ could฀be฀demonstrated฀that฀the฀activity฀of฀the฀monooxygenase฀system฀is฀induced฀only฀by฀a฀ smoking฀mother฀but฀not฀by฀a฀smoking฀father฀ [26] .฀The฀extent฀of฀induction฀was฀dependent฀ on฀the฀number฀of฀cigarettes฀smoked฀daily.฀Because฀of฀the฀lack฀of฀enzyme฀induction฀in฀the฀ liver,฀the฀placenta฀seems฀to฀play฀a฀major฀role฀in฀protecting฀the฀foetus฀from฀the฀toxic-prod- ucts฀of฀tobacco฀smoke฀which฀are฀degraded฀before฀they฀reach฀the฀foetus฀ [27] . Cadmium฀levels฀are฀elevated฀in฀smokers฀ [28,฀29] ,฀hCG฀secretion฀is฀reduced฀and฀tropho- blast฀proliferation฀is฀inhibited฀through฀interactions฀with฀calmodulin฀ [30] .฀Nicotine,฀Cd 2+ ฀and฀ polyaromatic฀hydrocarbons฀possibly฀also฀inluence฀oestrogen฀synthesis฀and฀metabolism,฀as฀ well฀as฀granulosa-luteal฀function฀ [31] .฀Isolated฀stem฀villous฀arteries฀from฀the฀placentas฀of฀ women฀who฀smoked฀heavily฀³15฀cigarettesday฀responded฀in฀vitro฀to฀endothelin-1฀by฀devel- oping฀lower฀tension฀compared฀with฀vessels฀from฀non-smokers;฀however,฀the฀maximum฀vaso- constrictive฀response฀to฀endothelin-1฀was฀more฀pronounced฀ [32] .฀It฀is฀concluded฀from฀these฀ experiments฀that฀the฀mechanical฀properties฀of฀stem฀villous฀arteries฀from฀heavy฀smokers฀are฀ altered฀and฀these฀changes฀may฀ultimately฀compromise฀foetal฀placental฀blood฀low฀and฀thereby฀ contribute฀to฀lower฀birth฀weight฀ [32] . Smoking฀is฀associated฀with฀increased฀Cd 2+ ฀levels,฀raised฀haematocrit฀and฀alterations฀in฀ the฀ine-tissue฀structure฀of฀the฀placenta฀smaller฀intervillous฀spaces,฀reduced฀foetal฀capillary฀ volume,฀leading฀to฀hypoxic฀states฀characterised฀by฀diminished฀O 2 ฀transfer฀ [17] .฀Placental฀ receptors฀for฀epidermal฀growth฀factor฀EGF,฀a฀potent฀mitogen฀for฀trophoblasts,฀are฀reduced฀ [31,฀ 33–35] .฀ Other฀ investigators฀ have฀ attributed฀ a฀ pivotal฀ harmful฀ role฀ to฀ CO฀ and฀ lead,฀ alongside฀numerous฀other฀harmful฀constituents฀of฀tobacco฀smoke฀ [36] .฀Measurements฀of฀ cadmium,฀zinc฀and฀copper฀levels฀in฀the฀placental฀tissue฀of฀women฀from฀Finland,฀Estonia฀and฀ St.฀Petersburg฀ [36] ฀reveal฀that฀placental฀concentrations฀of฀Cd 2+ ,฀Cu 2+ ฀and฀Pb 2+ ฀are฀already฀ markedly฀elevated฀in฀the฀irst฀trimester฀ [6] ,฀and฀a฀negative฀correlation฀was฀found฀between฀ placental฀Cu 2+ ฀levels฀and฀neonatal฀birth฀weight฀ [36] .฀The฀highest฀Cd 2+ ฀concentrations฀were฀ detected฀in฀samples฀collected฀from฀women฀living฀in฀St.฀Petersburg฀ [36] . The฀loss฀of฀EGF฀receptors฀because฀of฀benzo[a]pyrene฀is฀linked฀not฀only฀with฀reduced฀ trophoblast฀proliferation฀and฀hCG฀secretion฀ [37] ,฀but฀also฀with฀reduced฀c-myc฀expression฀ proto-oncogene฀ and฀ increased฀ transforming฀ growth฀ factor฀ TGF฀ b2฀ expression฀ [38] .฀ Tobacco฀smoke฀is฀therefore฀able฀to฀exert฀a฀deleterious฀effect฀on฀trophoblast฀gene฀expres- sion฀via฀EGF฀receptors,฀c-myc฀down-regulation฀and฀TGFb1฀up-regulation.฀Trophoblast฀ growth฀is฀also฀affected฀because฀of฀smoking-induced฀hypoxia฀see฀below฀ [31,฀39] . Inhaled฀tobacco฀products฀such฀as฀cadmium฀and฀benzo[a]pyrene฀are฀toxic฀substances฀that฀ act฀speciically฀on฀uterine฀villi,฀contributing฀to฀foetal฀hypoxemia฀and฀leading฀to฀miscarriage.

8.2 Complications of Pregnancy

It฀has฀been฀established฀for฀a฀number฀of฀years฀that฀women฀who฀smoke฀during฀pregnancy฀ give฀birth฀to฀a฀high฀proportion฀of฀neonates฀with฀low฀birth฀weight฀LBW฀or฀growth฀retarda- tion,฀sometimes฀with฀shortened฀pregnancies฀preterm฀deliveries,฀andor฀are฀more฀likely฀ than฀ non-smoking฀ pregnant฀ women฀ to฀ miscarry฀ due฀ to฀ premature฀ placental฀ abruption฀ Table฀ 8.2 ฀ [41] .฀Correlations฀have฀now฀been฀established฀in฀one฀study฀between฀reductions฀ in฀birth฀weight฀of฀up฀to฀500฀g฀and฀CYP1A1฀and฀GSTT1฀enzyme฀activity฀see฀Sect.฀ 5.2.3.2 ฀ in฀ Chap.฀ 5 ฀ [42] .฀ Genetic฀ alterations฀ in฀ the฀ two฀ enzyme฀ systems฀ are฀ linked฀ with฀ birth฀ weight฀reductions,฀as฀shown฀by฀the฀data฀summarised฀in฀Table฀ 8.3 ฀ [42] ,฀with฀the฀result฀that฀ an฀ association฀ between฀ the฀ genetic฀ changes,฀ resultant฀ metabolic฀ capacity฀ and฀ cigarette฀ smoking฀ may฀ be฀ assumed.฀ Despite฀ the฀ presence฀ of฀ adverse฀ genotypes,฀ reduced฀ birth฀ weights฀were฀not฀detected฀in฀neonates฀of฀non-smokers. Sequelae Risk฀odds฀ratio Percent฀of฀all฀cases Incidenceyear Tobacco-induced฀abortions 1.32 ฀ 3–8 19,000–141,000 Infants฀with฀low฀birth฀ weight฀LBW 1.99 11–21 32,000–61,000 Infant฀deaths฀due฀to฀adverse฀ perinatal฀effects 1.23 ฀ 3–8 ฀ 1,900–4,800 Sudden฀infant฀death฀ syndrome฀SIDS 2.98 22–41 ฀ 1,200–2,200 Table 8.2 ฀฀฀Sequelae฀of฀tobacco฀consumption฀in฀the฀USA฀ [40] Remarkably,฀the฀rate฀of฀pre-eclampsia฀has฀been฀reported฀to฀be฀lower฀in฀heavy฀smokers฀ than฀in฀non-smokers฀11.3฀vs.฀13.0;฀OR฀=฀0.85;฀CI:฀0.73–0.99.฀However,฀smokers฀ with฀pre-eclampsia฀had฀higher฀rates฀of฀infants฀with฀very฀low฀birth฀weight฀OR฀=฀1.85;฀ CI:฀1.55–2.20฀and฀higher฀rates฀of฀placental฀abruption฀OR฀=฀3.49;฀CI:฀1.65–7.28฀ [43] . More฀discriminating฀information฀on฀malformations฀is฀provided฀by฀a฀study฀from฀the฀ USA฀in฀which฀3,284฀live฀births฀of฀women฀who฀smoked฀were฀compared฀with฀4,500฀live฀ births฀of฀non-smokers.฀When฀all฀malformations฀were฀considered฀as฀a฀group,฀no฀increased฀ risk฀was฀associated฀with฀maternal฀smoking.฀However,฀when฀speciic฀malformations฀were฀ considered฀ separately,฀ signiicant฀ associations฀ with฀ maternal฀ smoking฀ were฀ found฀ for฀ microcephalus,฀cleft฀defects฀and฀clubfoot,฀but฀not฀for฀Down฀syndrome฀Table฀ 8.5 ฀ [48] .฀ Atrial฀septal฀defects฀are฀reported฀not฀to฀be฀attributable฀to฀smoking฀during฀pregnancy฀ [52] . One฀survey฀of฀12,914฀pregnancies฀and฀10,523฀live฀births฀has฀shown฀that฀the฀risks฀of฀spon- taneous฀abortion฀and฀congenital฀abnormality฀in฀smoking฀mothers฀are฀1.7-฀and฀2.3-fold฀higher,฀ respectively,฀than฀in฀non-smokers฀ [62] .฀Similar฀indings฀were฀reported฀in฀another฀study฀pub- lished฀in฀the฀same฀year฀showing฀that฀smokers฀20฀cigarettesday฀had฀a฀1.6-fold฀increased฀ risk฀of฀giving฀birth฀to฀an฀infant฀with฀congenital฀malformations฀ [63] .฀The฀infants’฀birth฀weight฀ is฀reduced฀ [64–67] ,฀and฀preterm฀deliveries฀are฀more฀common฀ [68] ,฀because฀of฀the฀possibility฀ of฀disturbances฀of฀placental฀maturation฀resulting฀from฀intrauterine฀O 2 ฀deiciency.฀As฀demon- strated฀in฀a฀group฀of฀770,744฀babies฀born฀in฀Germany฀in฀1999,฀154,149฀of฀them฀were฀born฀of฀ smoking฀ mothers฀ [2] .฀ A฀ dose-dependent฀ and฀ age-dependent฀ reduction฀ of฀ the฀ mean฀ birth฀ weight฀was฀calculated฀Fig.฀ 8.1 .฀It฀has฀also฀been฀suggested฀in฀this฀context฀that฀the฀infants฀ affected฀have฀a฀lower฀IQ฀ [69,฀70] ,฀as฀substantiated฀by฀a฀prospective฀study฀in฀19,117฀children.฀ Low฀IQ฀values฀were฀detected฀when฀no฀other฀neurological฀abnormalities฀were฀present.฀In฀a฀UK฀ study฀conducted฀in฀children฀aged฀9.4฀years฀whose฀mothers฀had฀smoked฀during฀pregnancy,฀no฀ adverse฀effects฀on฀IQ฀or฀cognitive฀development฀were฀detected฀compared฀with฀controls฀ [71] . A฀study฀conducted฀in฀227,791฀live฀births฀in฀Westphalia฀clearly฀showed฀an฀association฀ between฀ LBW฀ and฀ cigarette฀ consumption฀ during฀ pregnancy฀ 10฀ cigarettesday฀ [72] ฀ see฀Table฀ 8.4 .฀Similarly,฀smoking฀African฀American฀women฀from฀low-income฀groups฀ were฀reported฀to฀be฀more฀likely฀to฀have฀LBW฀2,500฀g฀and฀preterm฀37฀weeks’฀gesta- tion฀births.฀When฀lightsmokers฀were฀compared฀with฀non-smokers,฀the฀odds฀ratios฀were฀ 1.89฀CI:฀1.15–3.13฀for฀LBW฀births฀and฀1.74฀CI:฀1.00–3.02฀for฀preterm฀births.฀When฀ heavy฀smokers฀were฀compared฀with฀non-smokers,฀the฀odds฀ratios฀were฀3.03฀CI:฀1.90–4.86฀ for฀LBW฀births฀and฀2.60฀CI:฀1.55–4.35฀for฀preterm฀births฀ [74] .฀According฀to฀a฀Swedish฀ study฀ in฀ pregnant฀ women฀ who฀ smoked,฀ male฀ foetuses฀ were฀ affected฀ signiicantly฀ more฀ Enzyme฀system Genetic฀variant n Birth฀weight฀ reduction฀g OR฀95฀CI CYP1A1 None −377฀±฀89 2.1฀1.2–3.7 CYP1A1 AA 75฀AA −252฀±฀111 1.3฀0.6–2.6 CYP1A1 AAaa 43฀Aa,฀6฀aa −520฀±฀124 3.2฀1.6–6.4 GSTT1 Present −285฀±฀99 1.7฀0.9–3.2 GSTT1 Absent −642฀±฀154 3.5฀1.5–8.3 CYP1A1฀–฀GSTT1 AAaa฀+฀absent −1,285฀±฀234 p฀฀0.001 Table 8.3 ฀฀฀Inluence฀of฀genetic฀variants฀of฀CYP1A1฀and฀GSTT1฀on฀the฀birth฀weight฀of฀infants฀born฀ to฀174฀smoking฀and฀567฀non-smoking฀pregnant฀women฀ [42]