Intrahepatic Cholestasis of Pregnancy and Cancer: A Cohort Study

In ahepa ic Choles asis o P egnancy and Cance : A Coho S udy Su i-Tuulia Hämäläinen1,2*, Kaisa Tu unen1, Ka i J Ma ila1, Elise Kosunen1,3 and Ma kku Sumanen1 1Depa men o Gene al P ac ice, Facul y o Medicine and Li e Sciences, Uni e si y o Tampe e, Tampe e, Finland 2Janakkala Heal h Cen e, Tu enki, Finland 3Cen e o Gene al P ac ice, Pi kanmaa Hospi al Dis ic , Tampe e, Finland *Co esponding au ho : Su i-Tuulia Hämäläinen, Depa men o Gene al P ac ice, Facul y o Medicine and Li e Sciences, Uni e si y o Tampe e, Tampe e, Finland, Tel: +358368011; E-mail: [email p o ec ed] Recei ed da e: June 05, 2017; Accep ed da e: June 22, 2017; Published da e: July 3, 2017 Copy igh : © 2017 Hämäläinen ST, e al. This is an open-access a icle dis ibu ed unde he e ms o he C ea i e Commons A ibu ion License, which pe mi s un es ic ed use, dis ibu ion, and ep oduc ion in any medium, p o ided he o iginal au ho and sou ce a e c edi ed. Abs ac Objec i e: In a p e ious ques ionnai e s udy, mo e b eas cance s we e epo ed by women wi h in ahepa ic choles asis o p egnancy (ICP) han by he con ols. The aim o his s udy was o es ablish whe he ICP is associa ed wi h cance in he Finnish Cance Regis y da a, he s udy popula ion being he same coho as in he ques ionnai e s udy. Me hods: The s udy popula ion comp ised 571 women wi h ICP in a leas one p egnancy and 1,333 con ols om Tampe e Uni e si y Hospi al in Finland du ing 1969–1988. The cance da a we e ob ained om he Finnish Cance Regis y. The cance s we e classi ied by ICD-O-3 and diagnosed du ing he pe iod 1953−2013. Resul s: In he ICP g oup, he odds a io o cance s (OR 1.26, 95% CI 0.96–1.64), and b eas cance in pa icula (OR 1.36, 95% CI 0.91–2.03), was sligh ly highe han in he con ol g oup. Se en pe cen o he ICP g oup and 5.3% o he con ol g oup had b eas cance . Conclusion: Based on his s udy he e is no a signi ican associa ion be ween ICP and cance . Ea lie obse a ion in he ques ionnai e s udy ega ding associa ion be ween ICP and b eas cance canno be con i med by his egis y based s udy. Keywo ds In ahepa ic choles asis o p egnancy; ICP; Cance In oduc ion In ahepa ic choles asis o p egnancy (ICP) is a e e sible li e diso de wi h p u i us as he main symp om, especially on he palms and soles. An ele a ed se um bile acid and ansaminase concen a ion is also equi ed o diagnosis [1]. In Eu ope, he incidence o ICP is app oxima ely 1%, bu a es a y geog aphically [2]. In Finland, he incidence is app oxima ely 1.0−1.5% [3] and in Sweden he incidence is 0.5−0.75% [4]. Ho monal ac o s seem o con ibu e o he pa hogenesis o ICP [5,6]. Es ogen may pa icipa e in he de elopmen o choles asis [7] and p oges e one may impai hepa ic bile homeos asis [8]. Gene ic ac o s a e known o be in ol ed in he pa hogenesis; ICP is inhe i ed as a sex-limi ed dominan pheno ype and mul iple genes a e in luen ial [9]. Mul id ug esis an p o ein 3 (MDR3) is associa ed wi h up o 15% o ICP cases [10,11]. En i onmen al ac o s may also ha e a ole in he pa hogenesis o he diso de [12]. In addi ion, a posi i e amily his o y [13] and win p egnancies aise he isk o ICP [14]. Excessi e exposu e o endogenous es ogen o e he li e ime may be a causa i e ac o o b eas cance [15]. Ho monal, gene ic, and en i onmen al ac o s a e known o ha e an impac on he ae iology and pa hogenesis o cance s and ICP. Cance an igen 15-3 (CA15-3) is a glycop o ein commonly ound in b eas cance cells, and i s le els in se um e lec he amoun o b eas cance cells in he body. CA15-3 le els a e aised du ing p egnancy in gene al, bu hey a e highe in ICP p egnancies han in con ols [16]. In an ex ensi e egis y-based s udy, ICP was associa ed wi h an inc eased isk o la e hepa obilia y cance . Hepa i is C in ec ion was s ongly associa ed wi h li e cance , bu a e adjus ing o his diagnosis, women wi h ICP we e s ill a inc eased isk o li e malignancy. In addi ion, in a sepa a e analysis excluding all women wi h galls one disease o cholangi is, women wi h ICP had an inc eased isk o bilia y ee malignancies [17]. A low numbe o child bi hs has been associa ed wi h an inc eased isk o b eas cance . Since mo he s wi h ICP ha e been ound o limi hei child numbe mo e o en han con ols [18], i may be specula ed whe he his has inc eased he incidence o b eas cance s. P ima y heal hca e a anges almos exclusi ely ma e ni y ca e in he No dic coun ies [19]. In Finland heal h cen es main ain ma e ni y heal h clinics whe e a nu se o a midwi e and a Family Doc o a e esponsible o ca e [20]. The ma e ni y heal h clinics in p ima y heal h ca e usually de ec ICP. I a p egnan woman complains o p u i us he ALAT and bile acids alues a e sc eened. Ei he o hese alues being ele a ed he mo he is e e ed o an obs e ician [21]. I p u i us is in ole able he mo he is e e ed o he obs e ic clinic wi hou wai ing he esul s o he blood es . A ques ionnai e s udy obse ed ha ICP may be associa ed wi h an ele a ed isk o b eas cance [22]. Howe e , he s udy was based on subjec i e in o ma ion ob ained om sel - epo s. The aim o he p esen s udy was o in es iga e, using objec i e egis y da a, whe he ICP has an associa ion wi h b eas cance o o he cance s when using he same coho as he ques ionnai e s udy. Family Medicine & Medical Science Resea ch Hämäläinen e al., Fam Med Med Sci Res 2017, 6:2 DOI: 10.4172/2327-4972.1000216 Resea ch A icle OMICS In e na ional Fam Med Med Sci Res, an open access jou nal ISSN:2327-4972 Volume 6 • Issue 2 • 1000216 Ma e ial and Me hods All ICP p egnancies a Tampe e Uni e si y Hospi al (TUH) du ing 1969–1988 we e collec ed om he pa ien eco ds. F om 1969 o 1986, ICD-8 was used a TUH. Because ICD-8 did no include a p ecise code o ICP, we checked all he obs e ic codes ha migh con ain ICP: 637.9 Toxicosis NUD, 639.00 P u i us, 639.01 Ic e us g a is, 639.09 Nec osis acu a e subacu a hepa is, and 639.98 Aliae de ini ae. The ea e , we checked he w i en diagnosis behind he code, and i i e e ed o ICP, we included he case o u he selec ion. ICD-9 was used be ween 1987 and 1988, and i con ained he app op ia e codes 6467A Hepa osis g a ida um and 6467X Hepa opa hia alia. The diagnosis was e i ied om each pa ien eco d wi h he p esence o he main symp om o i ching and abno mal labo a o y es esul s. A leas one o he ollowing was equi ed: ASAT >35 U/l, ALAT >40 U/l, o bile acids 6 μmol/l o mo e. The s udy popula ion comp ised 687 ICP deli e ies. The da a included some women wi h epea ed ICP deli e ies and each o hese women was s udied as an indi idual case. The ICP g oup hus con ained 575 women. The p oceeding and ollowing subjec s in he ma e ni y wa d dia y we e aken as con ols o each ICP case. The e we e 1,374 con ols in o al. The g oups we e compa able ega ding age, educa ional le el, and body mass index. The deli e ies o mo he s wi h ICP ook place a ea lie ges a ional weeks han hose o he con ols. Fou women we e uled ou om he ICP cases and 41 om he con ols because o a missing pe sonal iden i y code. The inal da a comp ised 571 women wi h ICP and 1,333 con ols. The cance da a we e ob ained om he Finnish Cance Regis y in Janua y 2014 based on pe sonal iden i y codes. All physicians, hospi als, and o he ele an ins i u ions ha e had an obliga ion o epo e e y cance o he Finnish Cance Regis y since 1961. The da abase con ains all he diagnosed cance s and cance dea hs in Finland since 1961 and he mos o cance s since 1953, when sys ema ic cance egis a ion was s a ed [23]. The Finnish Cance Regis y also con ains in o ma ion on all dea h ce i ica es ha men ion cance . The Regis y akes no ice o he comple eness and accu acy o i s da a, and i s comple eness has been shown o be o e 99% [24]. The Regis y is upheld by he Na ional Ins i u e o Heal h and Wel a e o Finland. The s udy da a included all epo ed cance s o he coho du ing 1953–1960, all egis e ed cance s du ing 1961–2013, and he loca ion and beha iou o he cance . The cance s we e epo ed by ICD-O-3 opog aphical codes [25]. Women who had had mo e han one cance we e also included in he s udy. The cance s we e classi ied by ICD-O-3 codes in o la ge subg oups. Cance beha iou was classi ied as benign, unclea beha iou , ca cinoma in si u, o malignan . The da a we e analysed using he SPSS Sys em o Windows, Ve sion 22.0. The esul s a e p esen ed as equencies and pe cen ages. S a is ical signi icance was es ed wi h a chi-squa ed es . Bina y logis ic eg ession analysis was pe o med o ob ain odds a ios (OR) and 95% con idence in e als (CI). The dependen a iable was “ICP o no ”. T- es was pe o med o explo e di e ence ega ding age a he diagnose momen o cance . The coho did no ob ain in o med consen because he s udy is e ospec i e and does no ha e an e ec on ea men . The s udy has he app o al o he Regional E hics Commi ee o Tampe e Uni e si y Hospi al (R02149) and he Na ional Ins i u e o Heal h and Wel a e in Finland (THL/1051/5.05.00/2014). Resul s In he ICP g oup, 96 women (16.8%) had been diagnosed wi h a leas one cance , compa ed o 185 women (13.9%) in he con ol g oup. The di e ence was no s a is ically signi ican (p=0.098). Mo he s wi h ICP had a sligh ly highe isk o cance (OR 1.26, 95% CI 0.96–1.64) han he con ol mo he s. None o he mo he s wi h ICP and i een (1.1%) o he con ols had been diagnosed wi h wo o mo e sepa a e cance s (p=0.011). One o he con ols had had h ee sepa a e cance s. Th ee women had been diagnosed wi h a cance be o e labou and all o hem we e con ols. The occu ence o cance s is p esen ed in Table 1. B eas cance was he mos common cance in bo h g oups. The mo he s wi h ICP had a sligh ly highe isk o b eas cance (OR 1.36, 95% CI 0.91–2.03) han he con ol mo he s. B eas cance was diagnosed a a sligh ly olde age in he ICP g oup han in he con ol g oup bu he di e ence was no s a is ically signi ican . ICD-10 code Cance Mo he s wi h ICP n=571 Con ol mo he s n=1,333 Di e ence n % n % % uni s p- alue C50 B eas 40 7.0 70 5.3 1.7 0.133 C73- C75 Thy oid and o he endoc ine glands 6 1.1 5 0.4 0.7 0.075 C64- C68 U ina y ac 4 0.7 3 0.2 0.5 0.116 C42 Haema opoie ic and e iculoendo helial sys ems 2 0.4 2 0.2 0.2 0.382 C30- C39 Respi a o y and in a ho acic o gans 1 0.2 3 0.2 0.0 0.827 C40- C41 Bone and a icula ca ilage 1 0.2 3 0.2 0.0 0.827 C80 Unknown p ima y si e 1 0.1 1 0.1 0.0 – C00- C14 Lip, o al ca i y, and pha ynx 0 0.0 1 0.1 -0.1 0.513 C15- C26 Diges i e o gans 7 1.2 19 1.4 -0.1 0.731 C45- C49 Meso helial and so issue 0 0.0 1 0.1 -0.1 0.513 C43- C44 Melanoma and o he malignan neoplasms o skin 18 3.2 38 2.9 -0.1 0.721 C51- C58 Female geni al o gans 14 2.5 35 2.6 -0.1 0.826 C69- C72 Eye, b ain, and o he pa s o cen al ne ous sys em 3 0.5 8 0.6 -0.1 0.844 C77 Lymph nodes 2 0.4 7 0.5 -0.1 0.610 Table 1: The occu ence o cance s in mo he s wi h ICP and he con ols. Ci a ion: Hämäläinen ST, Tu unen K, Ma ila KJ, Kosunen E, Sumanen M (2017) In ahepa ic Choles asis o P egnancy and Cance : A Coho S udy. Fam Med Med Sci Res 6: 216. doi:10.4172/2327-4972.1000216 Page 2 o 4 Fam Med Med Sci Res, an open access jou nal ISSN:2327-4972 Volume 6 • Issue 2 • 1000216 Melanoma and o he malignan neoplasms o he skin as well as cance s o he emale geni al o gans we e among he mos common cance s in bo h g oups. Cance s o he hy oid and o he endoc ine glands and u ina y ac cance we e mo e common in he mo he s wi h ICP han in he con ols, bu he di e ences we e no s a is ically signi ican . O he diges i e o gan cance s, hepa obilia y cance was also examined sepa a ely. Hepa obilia y cance was ound in one mo he wi h ICP and among none o con ols. Mos o he cance s (nea ly 90%) we e malignan in bo h g oups (Table 2). The di e ence be ween he g oups was no s a is ically signi ican (p=0.758). Cance beha iou Mo he s wi h ICP (n=96) (%) Con ol mo he s (n=185) (%) Malignan 87.5 86.5 Ca cinoma in si u 6.3 5.4 Unclea beha iou 0.0 1.1 Benign 6.3 7.0 Table 2: Cance beha iou acco ding o ICD-O-3 among mo he s wi h ICP and he con ols. The mo he s wi h ICP had been diagnosed wi h cance a a sligh ly olde age, he mean age being 53.0 yea s in he ICP g oup and 51.8 yea s in he con ol g oup. The di e ence was 1.2 yea s (p=0.315). The mean age o mo he s who had no been diagnosed wi h cance was 61.5 yea s among ICP mo he s and 61.3 yea s among con ols in 31/12/2013. Discussion The ICP g oup and he con ol g oup e inced mino di e ences in mos o he s udy ou come measu es. The indings a e in ag eemen wi h o me obse a ions on he associa ion o cance and ICP. In he con ol g oup, he e we e women who had been diagnosed wi h wo o mo e sepa a e cance s, bu in he ICP g oup each woman wi h cance had been diagnosed wi h only one cance . ICP was associa ed wi h a sligh ly highe isk o cance , especially b eas cance . The aim o he p esen s udy was o es ablish whe he ICP is associa ed wi h an inc eased isk o cance s, and especially o b eas cance , which was he esul ound om he ea lie s udy based on sel - epo s. Despi e he small loss o cases, he da a we e adequa e. The da a ob ained om he Finnish Cance Regis y can be conside ed eliable. Medica ions may ha e an impac on he isk o cance . O e he pas decades, a ious ea men s ha e been used o ICP. We ha e no collec ed in o ma ion abou he medica ion o ICP among ou s udy popula ion, and consequen ly he ole o medica ion ega ding he isk o cance canno be e alua ed. A ecen Swedish s udy did no ind any clea associa ion be ween o e all cance and ICP [17], which is in ag eemen wi h ou indings. In he same s udy, an inc eased isk o la e hepa obilia y cance in women wi h ICP was ound (li e cance : HR 3.61; and bilia y ee cance : HR 2.62). In he a o emen ioned s udy, he occu ence o hepa obilia y cance s was small in he ICP g oup (0.1–0.2%). Based on he abo e s udy, he expec a ion alue o ind any hepa obilia y cance s in ou s udy was e y small. Howe e , one hepa obilia y cance was ound in ou ICP g oup, which exceeds he expec a ion alue. The e is highe isk o hepa obilia y disease and pa icula ly ch onic hepa i is among women wi h a his o y o ICP [26,27]. The la e disease causes li e ci hosis and is o en complica ed by hepa ocellula cance [17]. Also choleli hiasis and ch onic cholangi is a e associa ed wi h ICP [26,27] and a e associa ed wi h gallbladde and cholangiocellula cance [17]. The Swedish egis y s udy did no ind any associa ion be ween b eas cance and ICP (HR 1.03). In ou s udy, mo he s wi h ICP had a sligh ly highe isk o b eas cance han he con ol mo he s (OR 1.36), al hough he di e ence was no s a is ically signi ican . The occu ence o b eas cance was lowe in he Swedish popula ion (1.6%) han in ou Finnish popula ion. Women’s isk o ha ing b eas cance be o e he age o 75 is 9.9% in Finland and 9.6% in Sweden [28]. Ou longe ollow-up ime and he younge age o mo he s in he Swedish s udy migh explain he di e ence. Ne e heless, he coho should be ollowed e en longe because now he coho ep esen s hose who had been diagnosed wi h cance a a ai ly young age. P ema u e deli e y (ges a ion weeks <37) seems o inc ease he mo he ’s isk o b eas cance la e in li e [29]. Fo me ly, i has been ound ha ICP is associa ed wi h an ele a ed isk o deli e y in ges a ion weeks unde 37 [14]. I can be conside ed ha p ema u e deli e y may inc ease he numbe o b eas cance cases among ICP women. A ques ionnai e s udy obse ed ha he women wi h ICP epo ed mo e b eas cance (6.3% s. 3.7%, p=0.047) [22]. In ou s udy, b eas cance was ound among 7.0% in he ICP g oup and among 5.3% in he con ol g oup, he coho being he same as in he ques ionnai e s udy. In his egis y s udy, howe e , he di e ence be ween he g oups is no s a is ically signi ican . ICP has ound o ha e a mul i ac o ial gene ic base. I may be specula ed ha ICP is one exp ession o a la ge g oup o gene ic diseases. Ho monal ac o s may be ele an in he pa hogenesis o ICP and b eas cance [5,6,15]. I may be specula ed whe he he same ho monal ac o s ha e an e ec on bo h diseases. This is he i s Finnish egis y s udy on he po en ial associa ion be ween ICP and cance . Acco ding o he w i e s’ knowledge he e is only one egis y based s udy in es iga ing he associa ion be ween ICP and cance [17], and he e o e he indings in his s udy may be conside ed unique. Howe e , o me obse a ions ega ding he associa ion be ween ICP and b eas cance in he ques ionnai e s udy could no be con i med by his egis y based s udy. A la ge numbe o ICP women and a longe ollow-up ime o he coho migh be needed o con i m he esul s. Based on his s udy doc o s do no ha e o change hei ea ing s a egies and sc een cance s because a woman has a his o y o ICP. Ci a ion: Hämäläinen ST, Tu unen K, Ma ila KJ, Kosunen E, Sumanen M (2017) In ahepa ic Choles asis o P egnancy and Cance : A Coho S udy. Fam Med Med Sci Res 6: 216. doi:10.4172/2327-4972.1000216 Page 3 o 4 Fam Med Med Sci Res, an open access jou nal ISSN:2327-4972 Volume 6 • Issue 2 • 1000216 Acknowledgmen s The Cen e o Gene al P ac ice o he Pi kanmaa Hospi al Dis ic unded he s udy by se ling he dues om he Na ional Ins i u e o Heal h and Wel a e in Finland and he Finnish Cance egis y. We a e g a e ul o he Na ional Ins i u e o Heal h and Wel a e in Finland and he Finnish Cance Regis y o hei consen o use he egis y da a. Con lic o In e es The au ho s ha e no con lic s o in e es . Re e ences 1. Williamson C, Geenes V (2014) In ahepa ic choles asis o p egnancy. 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(2016) NORDCAN: Cance Incidence, Mo ali y, P e alence and Su i al in he No dic Coun ies, Ve sion 7.3. Associa ion o he No dic Cance Regis ies. Danish Cance Socie y. 29. Hsieh CC, Wuu J, Lambe M, T ichopoulos D, Adami HO, e al. (1999) Deli e y o p ema u e newbo ns and ma e nal b eas -cance isk. Lance 353: 1239. Ci a ion: Hämäläinen ST, Tu unen K, Ma ila KJ, Kosunen E, Sumanen M (2017) In ahepa ic Choles asis o P egnancy and Cance : A Coho S udy. Fam Med Med Sci Res 6: 216. doi:10.4172/2327-4972.1000216 Page 4 o 4 Fam Med Med Sci Res, an open access jou nal ISSN:2327-4972 Volume 6 • Issue 2 • 1000216