DISEASE OF THE MONTH314.full

8/12/2019 DISEASE OF THE MONTH314.full

1/8

IS E SE O F TH E M O NTH

H yperten sion in P regnan cyM A R K S . P A L L E RUnivers ity o f M in neso ta , M inneapo lis , M inneso ta .

N otw iths tan d ing its ob v iou s bene fits , p reg nancy w ill rem a in arisky bu sine ss a s w e en te r the nex t m illenn iu m ( 1 . N o do ubt,m an y o f the h isto r ica lly sign ific an t adv erse ou tco m es of p reg -n an cy have been e lim ina ted b y m ode rn m ed ical ca re. F o rexam p le, acu te ren a l fa ilu re o ccu rr ing in p regnancy as a con-seq uence o f sep tic abo rtio n , ab ru p tio p bacen tae , an d ev en p re -ec lam ps ia, ha s a lm o st d is ap peared as a c lin ica l en tity . N eve r-th eb es s, m a te rn al death co m plica te s ch ild b ir th in ap prox im ate lyn ine o f I 00 ,0 00 de live rie s . T h e th ree lead ing cause s o f m a ter-n al dea th a re p regn ancy-indu ced hyp ertension , hem orrhage ,and p u lm o na ry em bo lism . H yp ertension com plicate s an esti-m ated 6 to 8% o f a ll p reg nanc ie s . M ore im portan tly , hy pe r-ten sion is re spo nsib le fo r approx im a tely 1 5% o f m a terna ldeath s. In add itio n , alm ost o ne -q ua rte r o f p regnan t w om enrequ ire ho sp ita liza tion fo r co m plica tions be fo re de live ry , rep -re sen ting a su bstan tia l hea lth ca re burden . F or the nephrob og ist,the im pact o f p reg nancy o n p reex isten t ren al d isease o r ch ron ichypertens io n w ill be encou n te red m ore o ften than new cases ofrena l d isease deve lop ing d e n ovo during pregnancy . H o w ev er ,p regn ancy is o f ten the f irs t sus tain ed con tac t be tw een yo ungw o m en and the health ca re sys tem . T he refo re , a sym p tom a ticrena l d isease o r h ype rten sion m ay be recogn ized in itia lly d u r-ing a p reg nancy .

H yper ten sion in P regn an cyH y pertens ion m ay b e c las sified as ch ron ic if it is recog n ized

be fo re 20 w eeks o f gesta tion o r a s p regn an cy -in duced if itoccu rs o n ly in the secon d h alf o f p regnancy . T h is sepa ra tion isc lin ica lly use fu l b ecause a lm ost a ll hy perten sion occurring inthe firs t ha lf o f p reg nancy is a resu lt o f un de rly in g ch ron ichyp ertension (es sen tia l h ype rten sion or seco nda ry hy pe rten -sion due to hy pera ldoste ron ism or pheochrom o cy tom a) or re -nab d isease. H ype rten sion deve lop in g in the second ha lf o fp reg nancy is m ore co m plex and is th e re su lt o f e ithe r a p reg -nancy-spec ific p rocess o r a com p lex in terp lay o f p regn ancyw ith rena l d isease or chro n ic hy perten sion resu lting in ex acer-ba tion of h ype rten sion .

N orm a l p reg nancy is cha rac te riz ed by a dec rea se in pe rip h -e ra l va scu la r re sis tance an d , to a le sse r ex ten t, a dec rea se inb loo d pres su re, w h ich occu r so on a fte r co ncep tion . T h is de -crease in v ascu la r resistance is due to increased syn thesis o fvasod ila to ry pros tag lan d ins, pa rticu la rly pros tacy clin . and en -

C o rrespo ndence to D r. M ark S . Pa lle r. U nivers ity of M inn eso ta . 420 D elaw areS tree t S E ., B ox 736 . M inneapo lis, M N 55455 .l()4 6- 66 73 /0 90 2-0 3 1 4$ 03 .0 0/( )

Journa l o f th e A m erican Soc ie ty of N ep hro logyC opyr igh t tO 1998 by th e Am er ican Soc iety o f N ephro log y

do the lial-de r ived n itr ic ox ide . T h ese vasod ilato rs also en gen-de r re sis tan ce to circu la ting v asocons tric to rs such as an g io ten -si n II and n orep inephrine , an d to loca lly p rod ucedvasocons tr ic to rs such as end o the lin . A fte r an in itia l d ecrease inb lood pres su re to ave rage va lues o f I 0 3 1 1 m m H g sys to licand 56 1 0 m m H g d ias to lic in the firs t trim ester , b lo odp re ssu re beg in s to inc rea se slig h tly af ter the 2 8 th w eek o fges ta tion . A lth ough 14 0 /90 m m H g is a co nven ien t c rite rion fo rep id em io log ic stu d ie s , pe rin a tal m orta lity inc rea se s fo r eachinc rem en t in b lo od p re ssu re , pa rticu la rly w hen d ia sto lic b lo odp re ssu re exceeds 85 m m H g. S im ila rly , pe rin a tal m orta lity in -c rea se s w hen m ean arte ria l p re ssu re is g rea te r than 82 m m H ga t m id -pregnancy or grea te r than 92 m m H g at the b eg in n ing ofthe th ird trim es te r. B ecause a b lood p ressure o f 1 20 /80 m m H grep re sen ts a m ean a rter ia l p re ssu re o f 9 3 m m H g , it is app aren tth at b lo od pressu re va lue s d uring pregnancy m u st be in te r-p re ted d iffe ren tly than va lues in the no npregnan t sta te . P rev i-o usly , the A m erican C olleg e of O bste tric s and G yn eco lo gycon sidered a pregn an cy-re la ted increase in systo lic b loo d p res-su re of 30 m m H g or pregnancy-re la ted in crease in d iasto licb lood pre ssu re o f 15 m m H g as a lso rep re sen tin g h ype rten sionin p regnancy . T hese crite ria h av e been ab an doned b ecause ofthe co nsiderab le variab ility of b lood pressure in norm oten sivew o m e n .Endoth elia l C ell In ju ry and P regn an cy-R ela tedDiseases

A varie ty o f d isea se s o f relev an ce to th e nephro lo g ist w hosem an ife sta tion s in clu de conseq uences o f d iffu se en do th elia l ce llin ju ry occu r d u rin g pregnancy . Po stpa r tum acu te ren al fa ilu re ,a lso k now n as po stpartum hem oly tic u rem ic syndrom e, is on esuch cond ition . T h is d isease , charac te rized by hy perten sionan d coagu la tion abn orm alitie s , inc lud ing m ic ro an g io pa th ic h e -m oly tic an em ia , occu rs 1 o r 2 d ay s to seve ral m on ths af te rde live ry . I ts m a jo r m an ifes ta tio n is th rom b o tic m ic roan g io -pa th ic acu te rena l fa ilu re . Pos tpartum acu te rena l fa ilu re hasm any s im ila ritie s to th rom b otic th rom b ocy topen ic purpura andhem oly tic u rem ic syn dro m e . O f g rea t in te re st, p reec lam psia ,th e H E L L P sy ndrom e (hem o lysis , e leva ted live r enzym es, lo wp late le ts) , and acu te fa tty live r o f p regnan cy a lso have fea tu resco nsisten t w ith endo the lial in ju ry . T h is su ggests the p ossib ilityo f a con tinuu m of d is ea se re su lting fro m end o the lia l cell in ju ryduring preg nancy , pe rhaps in itia ted th ro ugh d istinc t p ath w ay s.W hy th e endo the lium sho u ld be so suscep tib le to in ju ry duringpreg nancy rem a ins un clea r. A fo rm of hem o ly tic u rem ic syn -d rom e sim ilar to po stpa r tum acu te ren al fa ilu re occu rs inw o m en rece iv ing o ra l co n tracep tive s. T h is fin d ing sug gests aho rm on a l e tio log y fo r the endo the lial suscep tib ility to in ju ry .


2/8

Pregn an cy : A R isky B u siness

T he S hw artzm an reac tio n tha t occu rs a fte r ad m issio n of endo -tox in to expe rim en ta l an im a ls is en hanced w hen an im als a rep reg nan t. A p ossib le ex p lana tion fo r tha t ph enom en on is anim pa ired cap acity o f endo the lial ce lls to syn th es ize n itr ic o x ided urin g pregn ancy . Im p a ired en do th elia l syn th esis o f n itr ic ox -ide and p ro stacy clin th en pred isp ose s to vasocon stric tion an dcoagu lat ion .

Preec lamps iaP reec lam psia, a life -th rea ten ing illness spec ific to preg -

nancy , is poo rly u nders to od . M ajor m anifesta tions of p re -ec lam psia inc lude h ypertensio n , edem a, p ro te inuria , an d se i-zu re s. T he d isease is te rm ed ec lam ps ia w hen se izu re s occu r,b u t th is d istin ctio n is no t im p ortan t b ecause d ea th d ue tocereb ral h em orrh ag e or ca rd iac fa ilu re can occu r in th e absen ceo f se izu res . P reec lam psia is a fa sc ina ting d isea se because o f itsas soc iatio n w ith firs t p reg nanc ies an d co m plica ted p reg nan-c ies . D epen d ing on th e p opu la tio n surveyed , p reec lam psiacom p lica te s b e tw een 5 and 22 % of preg nanc ies . In ad d ition tonu llip a rity , o ther risk fac to rs fo r the deve lopm ent of p re -ec lam psia inc lude age grea te r th an 40 years (advanced in te rm sof rep rod uc tive age ) , fam ilial h is to ry o f p reg nancy-indu cedpreg nancy h ype rten sion , sm ok ing , o besity , and d iabe tes m e l-litu s . P regnan cie s co m plica ted by feta l hyd ro ps. m u ltip le ges-ta tion , p reex is ting h ype rten sion . an tipho sph o lip id sy ndrom e ,rena l d isea se , an d vascu la r d is ea se a re a lso at inc rea sed risk o fpreec lam psia (T ab le 1 . T he rela tive risk o f p reec lam psia de -v elo p ing in w o m en w ith ch ro n ic ren al d isea se is 20 to 1 . an dthe r isk o f p reeclam p sia deve lop in g in w om en w ith e ssen tia lhyp ertensio n is 1 0 to I . In the se instances, p reec lam psia a ffec tsm ultipa rous , as w e ll a s nu llipa ro us, w om en . M oreo ve r, p re -ec lam psia com p lica ting th ese cond itions m ay deve lop earlierthan 32 w eeks o f g es tatio n , w h erea s usua l p reec lam psiaaffec ting nu llip arou s w o m en deve lops in the th ird tr im ester(usu a lly a fte r 32 w eek s o f gesta tion ). O n e sho u ld be ale r t to th eposs ib ility tha t p reec lam p sia occasio na lly p re sen ts a s late as 48hou rs po stpa rtu m.

T he clin ica l m an ife sta tion s o f p reec lam p sia su ppo rt th e con -ten tion tha t th is is a sys tem ic d isea se . H ype rten sion is the m o stp rom in en t fea tu re o f p reec lam psia an d m ay b e seve re. H y pe r-

Tab le 1 . R isk fac to rs fo r the dev elo pm en t o f p reeclam p siaNu ll ipar i tyA g e grea te r than 4 0 y ea rs (advanced ag e in rep ro duc tive

t e r m s )F am ilial h is to ry o f p reg nancy-ind uced p regn an cy

hypertensionO besi tyD iabe te s m ellitu sF e tal h ydropsM ultip le g es tatio nHypertensionR ena l d isea seA n tipho sph o lip id sy ndrom eV ascu la r d is ea se

tension is caused b y an increase in periphera l vascu la r res is -tance an d is assoc iated w ith overac tiv ity of the sy m path e ticne rvou s system . A bno rm alitie s in pe rip he ra l va scu la r reac tiv itycan be d em ons tra ted b efo re the d ev elo pm en t o f ov ert h ype r-tension . O rd in ar ily in p regnancy there is a sh ift in prod uc tio no f vasoac tive subs tan ces by the end o the lium , fav oring v aso d i-ba tion . T h is inc rease in produ ction of pros tacy clin and n itrico x ide causes pregn an t w om en to be less sen sitive to the pressore ffec ts o f sub stances such as ang io tensin II. In w om en d es tinedto becom e preeclam ptic in the th ird trim este r. loss o f th is usua lres is tance to the pressor e ffec ts o f in fu sed ang io tensin II can bedem o nstra ted in m id -p regnancy w hen b loo d p re ssu re is stilln o r m a l .

V asoco nstric tio n in preec lam p sia m ay a lso cause a decreasein card iac ou tpu t an d a d ec rea se in rena l b lood flow an d G F R .T h is d ecrease in rena l b lood flow is respons ib le fo r a rise inp lasm a u ric acid , w hich usua lly o ccu rs in ad vance of anychanges in se rum crea tin ine . D ecreased urate c lea rance resu lt-ing in hy peruricem ia is a usefu l c lin ica l find ing tha t can serveto d iffe ren tiate p reec lam psia fro m o the r cau se s o f hy pe rtensio ntha t m ay occur during pregnan cy . B ecause o f p lasm a volum eexpans ion tha t occu rs during norm al pregn an cy , serum uricac id beve ls a re be tw een 2 .5 and 4 m g/d l in pregn an cy . A serumuric ac id leve l g reate r than 5 .5 m g/d l is con sisten t w ith p re -ec lam p sia . and va lues exceed ing 6 .0 m g/d l su ggest m ore se ri-ou s d isease . O ther m anifes ta tions o f preec lam psia a ffec ting th ek idn ey inc lude pro te inur ia , in creased seru m crea tin ine , and insev ere p reecbam p sia o lig uria . A lth ough pregnancy causes asm all in crease in the frac tio na l excre tion of a lbum in , 2 4-hou rurina ry excre tio n of p ro te in shou ld no t exceed 250 rng . P ro te inexc re tion in ex cess o f th is am o un t su ggests e ithe r rena l d isea seor preecbam psia (T ab le 2).

W o m en w ith p reec la rn psia have sym p tom s th at inc lud e ap -preh en sion : v ision prob lem s: and headache and ep igas tric d is -com fort re la ted to neuro log ic and hepa tic inv o lvem en t, re spec -tive ly . F ind ings on phys ical exam in ation in add ition tohy perten sion inc lude seg m en ta l a rte rio la r n ar row in g on fundu -sco p ic exam ina tion and rales and o ther phy sica l find ings con-s is ten t w ith cong estive heart fa ilu re. S igns of cen tra l ne rv oussy stem irr itab ility in clu de hyp e rac tiv e d eep tend on re flexes an dgenera lized se izures. A ltho ugh periphera l edem a a t one tim ew as cons id ered a requ irem en t fo r the d iagn osis o f p reeclam p-s ia , th is f in d ing h as little p red ic tive va lu e . U p to 8 3% ofhea lthy . p regnan t w o m en deve lop loca lized edem a a t som etim e d uring pregnancy . A s m any as 10% of pregnan t w om endeve lop g en era lized edem a w ithou t o th er ind ication s of d is-ease . T here fo re , edem a d oes n o t p red ic tab ly d iffe ren tia te p re -ec lam p sia from un co m plica ted preg nancy o r from pregn ancycom plica ted b y chron ic hy perten sion or ren al d isease .

L aborato ry f ind in gs in p reecbam ps ia , in add itio n to th e e le -va tions in se rum uric ac id and creatin ine d iscussed abo ve ,inc lude ind ica to rs o f a m icroang iop ath ic hem oly tic anem ia .T hese inc lude fragm en ted red ce lls on pe rip he ra l sm ea r , in -creased lacta te dehy drogenase , and th rom bocy top en ia . H epa-toce llu la r dy sfunc tion can be recogn ized by an e leva tion inlive r enzy m es . T he H E L LP sy ndrom e (/iem olysis , e leva tedlive r enzym es, lo w pla te lets ) is a c lin ica l syndrom e tha t rep-


3/8

3 Jo urna l o f th e A m erican S oc ie ty of N ephro logy

Tab le 2 . C lin ica l featu re s o f h ype rten sive d iso rde rs in p regnan cy a

Featu reE ss en tia l H yp er te ns io n R ena l D isease P reec lam psia

1s t H alf 2nd H alf 1st H alf 2nd H alf 1st H alf 2n d H alfH yper tens ionPro teinu ria

1- -

1-

-

-

++

Microscop ichematu ria

1 - 1 -

Increased 1 - 1 - 1-crea tin ine (> 1 .0mg/d l)

Inc rea sed u ric - - +ac id (> 4 m g/d l)

Coagu lat ionabnormali t ies

- - + /-

a W om en w ith essen tia l hy pe rtensio n o r ren al d isea se are a t inc rea sed risk o f deve lop in g superim posed preec lam psia w ith a ll o f theas soc iate d find ings . . usua lly absen t: +, usua lly presen t: +/- . m ay be presen t.

re sen ts one fo rm of seve re p reeclam p sia and o ccurs in 2 to I 2%of case s o f p reec lam psia . A s the seve rity o f p reec lam psiainc reases , m an ifes ta tions of en do the lial ce ll in ju ry are m oreobv iou s. Th us, h ypertension is m ore sev ere and coagub opa thyan d live r fun ctio n abn orm a litie s a re m ore p rom in en t.

TherapyPreven t ion

T he h isto ry o f stu d ie s o f p rop hy lac tic trea tm en ts fo r p re -ec lam psia is an en gag ing o ne . In itial sm all-sca le , rando m ized ,co n tro lled tr ia ls and m eta -an aly se s o f the se tria ls w e re q u itep ro m ising . H ow eve r. la rge -sca le , rand om ized , con tro lled tr ia lshave su ggested e ithe r a m ore lim ited ro le fo r p reven tive the r-ap ies (in the case of low -dose asp irin ) o r non e a t a ll (o ra lca lc ium supp lem enta tion ). P reg nancy tria ls h av e ap tly d em o n-s tra ted the lim ita tion s o f conc lus ions based on m eta -an alyses.

L o w -do se asp ir in w as in itia lly su ggested to b e an id ealp rev en tive treatm en t fo r p reec lam psia p red ica ted on the cu rren tu nde rstand in g of the pa tho phy siob ogy o f th e d isea se. W ithrega rd to p ros tag lan d in p ro duc tion . p reeclam p sia is cha rac te r-iz ed by a sh if t aw ay from th e v asod ila ted s tate o f no rm alp reg nancy . T he re fo re , in p reec lam psia the re is le ss p rodu ctio nof p ro stacy clin and prostag land in E and greate r p rodu c tio n ofth rom b oxane com p ared w ith n orm a l p reg nancy , at lea st a ses tim a ted from c ircu la ting leve ls o f the se v asoac tive p rosta -g land ins. It w as reasoned th at low -dose asp irin w ould reducep la tele t-de riv ed prod uc tion o f th rom b oxane w h ile no t in terfe r-ing w ith en do theb ia l sy n thesis o f p rostacyc lin an d p rostag lan-d in E . T h e ne t e ffec t o f low -dose asp irin the rap y w o u ld be tore sto re vascu la r tone tow ard a m o re vaso d ila ted cond itio n .

T he ea rliest s tu d ie s o f low -d ose asp ir in to p rev en t p re -ec lam ps ia eva lua ted w om en w ith an inc reased risk o f d ev el-op in g the d isea se . F o r exam p le , in th e 198 9 stud y o f S ch iff etal . w om en w ere se lec ted fo r s tudy b y the p re sence o f a p ositivero llo ve r te st, a te st tha t sugg es ts inc rea sed sensitiv ity to an g io -ten sin II and there fo re a h igh risk of deve lop ing preec lam p sia(2 ). O the r ea rly stu d ie s w ere pe rfo rm ed in co horts a t h igh risk

o f deve lop ing p reec lam psia becau se o f a h isto ry o f in trau ter ineg row th re ta rd atio n , p rev iou s p regn an cie s w ith p reec lam p sia, o rth e p re sence o f ch ron ic hy pe rtensio n (3 ,4 ). T hese stu d ie s in -d iv id ua lly and a m eta -ana ly sis com b in in g them sugges ted th atlow -d ose asp irin in w om en a t r isk fo r p reg nancy-indu ced hy -p ertension redu ced the o ccu rren ce o f p reec lam psia an d sev erein trau te rine g ro w th re ta rd atio n (5 ) .

S ubsequen t, rando m ized , p rospec tive tria ls eva lua ted m uchla rger num bers o f w om en and those a t low or m in im al risk ofd eve lop in g preec lam psia . F o r exam p le, the 1 993 stud y by S iba ie t a l. eva lua ted 3 1 35 w om en in th eir f irs t p regn an cy b u tw itho u t o th er r isk fac to rs fo r the deve lop m en t o f p reeclam p sia(6 ) . T ha t stu dy sho w ed th at o ve ra ll, low -d ose asp ir in had asm all b u t s ig n ifican t ef fect in red uc ing the inc idence of p re -ec lam psia . A su bgroup ana lys is sho w ed tha t w o m en w h osein itia l sys to lic b lood pressu re w as g reate r th an 1 20 m m H g hada m ore d ram atic red uc tio n in th e inc idence of preec lam p sia of53 . T he C L A S P stud y o f 93 64 w om en fo und no sign ific an tredu ction in the in cid en ce o f preec lam p sia in w om en w ho w eretrea ted w ith 60 m g of asp irin beg in n in g be tw een the 12 th an d32 nd w eeks o fg esta tion (7 ). T he E C P P A study o f 10 09 w om enin B raz il used a sim ilar p ro to co l an d fo und n o benefit o flow -d ose asp irin to p reven t p reec lam ps ia (8 ) .

S eve ral tren ds show w h y the in itia l en th usia sm for low -doseasp irin has w aned . T he earlie s t stud ies o f low -do se asp irinw ere used in w om en at m odera te -to -h igh risk of deve lop ingpreec lam psia . In genera l, these s tu d ies used doses of asp iringrea te r than 60 m g per day (7 5 to I 50 m g da ily ), an d asp irinthe rapy w as in itia ted before 20 w eeks o f gesta tio n . M o re recen tstud ies used low er doses of asp irin , en ro lled w om en a t low errisk fo r p reec lam psia , and in itia ted therapy as la te as 32 w eek so f gesta tio n . C urren tly , seve ral la rg e -sca le tria ls a re und er w ayth at w ill ev a lua te the use o f low -do se asp irin in w o m en at h ig hrisk o f d ev elo p ing p reec lam psia . U n til the se stud ies a re com -p leted . th e fo llow ing seem s to be a conserva tive recom m end a-tio n fo r the use o f a sp irin . W om en at the h igh est r isk o fd eve lo p ing preec lam p sia can be treated w ith lo w -d ose asp irin


4/8

Pregn ancy : A R isky B usin ess 317

in th e h ope o f p reven ting p reec lam psia us ing d oses 1 00 m gda ily . T he safe ty of low -dose asp irin in these w om en is n olonger co n tested . S ev eral o f the recen t la rge-sca le tria ls ev al-ua ted sa fe ty v ery ca refu lly and fou nd no inc rea sed inc iden ce o fb leed ing , ab rup tio p lacen tae , o r o ther adverse e ffec ts, con tra ryto an ecd o ta l repo rts from earlie r sm a ll s tu d ie s (9 ,10 ). B ecau seh ig h -risk w o m en m ay deve lop early -on set p reeclam p sia (be -fo re 30 w eeks gesta tion ) if lo w -do se asp ir in is used , it sh ou ldbe in itia ted be tw een 10 and 14 w eeks of gesta tion . W om enco nsid ered a t h ig h risk fo r p reec lam psia inc lude tho se w hohave chron ic rena l d isea se , pa rticu la r ly w ith hy pe rtensio n ,p ro te inu ria , o r rena l in su ff iciency , a s w e ll a s w om en w ho havea h is to ry of prev io us m u ltip le pregnanc ies com plicated b yin trau te r ine g ro w th reta rda tion or p reeclam p sia .

C a lc iu m supp lem en ta tion fo r p ro phy lax is o f p reeclam p siahas a s im ila r h is to ry of d im in ished ex pec ta tions . O rig ina l stud-ies sugges ted tha t 2 gram s of e lem en ta l ca lc ium daily w ou ldreduce th e in cid ence o f p reec lam psia . In 19 91 , B e lizan et al .repo rted bene fic ia l e ffec ts o f calc ium in 1 194 nu llip arou sw om en (1 1). C a lc ium w as adm in is tered beg inn ing the 2 0 thw eek o f p regnancy . Sev era l add itio na l sm a ll-s ca le stud ies , a sw e ll a s a m e ta -ana lysis co m bin ing all s tud ie s pe rfo rm ed be fo reM ay 199 4 , su ggested tha t ca lc ium supp lem enta tion reducedth e r isk o f p reec lam psia b y 62 % (12 ). U nfo rtuna te ly , th e m o strecen t large -sca le tr ial o f calc ium supp lem en ta tio n in 45 89n u llipa ro us w o m en repo rted b y L ev ine e t a l. revea led nob en efic ial e ffects o f ca lc ium (1 3). A ga in , the se fin d ing s seemm o st secu re fo r w o m en at lo w risk o f deve lop ing preec lam psia .It is po ssib le th at p rev io us sm all s tu d ie s pe rfo rm ed a t a sin g lecen te r had eva lu ated w o m en at m o de ra te o r h igh risk fo r thedeve lop m en t o f p reeclam p sia . In th e absen ce o f c lue s a s tow hich w o m en sh ou ld rece ive ca lc iu m supp lem enta tio n , cal-c ium canno t be reco m m end ed fo r p rop hy lax is o f p reec lam ps iaa t th is tim e .

M anag em en tT he tim e-te sted , de f in itive trea tm en t fo r p reec lam psia is

de live ry . F o r w om en a t term , th is do es n o t rep re sen t a m a jo rp rob lem . W hen preec lam psia occu rs b etw een the 3 2nd and34 th w eeks of ges ta tion , o bste tric ians h av e som e flex ib ility .B ecause lon g-te rm fe ta l ou tcom e is lik ely to be goo d , de liv erys till rem ains a feas ib le o p tion . H ow ever, if p reec lam p sia is no tsevere , co nserv ative therapy cons isting of bed res t and an tihy-pertensive therapy can be un dertak en . Fe ta l ou tcom e is lessw ell gua ran teed at 28 to 3 4 w eek s o f g estatio n . If p reec lam psiao ccu rs a t th is tim e , it is reason ab le to a ttem pt m edica l m an-agem ent. It m us t be no ted tha t experience w ith such an ap-proach is lim ited . C o nse rv ativ e m an ag em en t be tw een 1 8 an d2 8 w eeks o f gesta tion h as been deba ted , w ith som e stu d ie ssugg es ting te rm ina tio n o f preg nancy a t the exp ense of the lifeo f th e fe tus to p reven t m a te rn al m orb id ity and o the rs su gg est-in g th a t an in itia l attem p t a t conse rva tive m anagem en t w illo ccas io na lly resu lt in pro longa tion of pregnancy w ith an u lti-m ate ly accep tab le ou tcom e . M ost w ou ld ag ree tha t p regn ancyshou ld be term in ated if p reec lam psia deve lop s be fo re the 1 8 thw eek of g es ta tion .

H y pertensio n com p lica ting p regn an cy rep resen ts a risk fo r

b o th the m other and th e fetus , bo th of w ho m m ust b e cons id -e red w hen se lecting therapy . H ypertens io n shou ld be trea ted top reven t m a te rn al m orb id ity and m o rta lity d ue to cau se s su ch asce reb ra l hem orrhage . T he effec t o f an tihyp e rtensiv e the rap y onfe ta l ou tcom e is less c lea r, and there is co nsiderab le d eb ate asto how ag gress ive ly b lood pressure shou ld be trea ted . A rgu ingaga inst aggressive an tihypertens ive therapy is the fea r tha tu te rop lacen ta l b lood flow w ill be com prom ised if m ate rna lb lo od p re ssu re falls too qu ick ly because o f a lim ited ab ility o fthe p lacen ta to au to regu la te b lood flow . D ias to lic b lood pres-su re go als have ranged from 90 to 1 10 m m H g, d en o ting thelack of unan im ity of op in ion . T he nu m ber and s ize of pro spec-live , random ized , con tro lled tria ls o f an tihy perten sive th erapyfor w om en w ho deve lop hypertens ion in the th ird tr im es te r a reac tu a lly qu ite lim ited . M o st s tud ies do su ggest tha t fe tal m or-b id ity and m o rtality can b e reduced w hen trea tm ent is p ro v idedfor d iasto lic b lood pressu res > 90 m m H g. T he ou tcom es tha tcan be expec ted b y trea ting h ypertension in the th ird trim es te rinc lu de redu c tion in the inc idence of prem aturity , in trau te rinegrow th re ta rd ation , and perina ta l death . F or exam p le , P h ipparde t a l. aggressive ly trea ted p regnancy-ind uced hypertens io n inw o m en w ith p rev io usly n orm a l b loo d p re ssu re w ho se m eanb loo d pressu re rose to 1 26 /82 m m H g w ith e ithe r c lon id ine (andhydralaz ine if needed) or p lacebo 14). A ntihyp er tens ive th er-ap y redu ced th ird trim es te r com plications and prem atu rity by80% . T hose stud ies tha t have dem on stra ted im proved fe ta lou tcom e have institu ted an tih ypertensive therapy in the seco ndor th ird trim es te r o f p regnancy . R esu lts m ay no t be com parab lew h en an tihyp ertensiv e the rap y is begun in the f irs t trim este r(see be low ).

T reatm en t o f m ild hy pe rtens ion (d ia sto lic b lood p re ssu re< 95 m m H g ) usu ally com m ences w ith b ed re st. O ne needs toascerta in tha t the re is n o ev idence of se rious d isease such aspro teinu ria (> 50 0 m g/24 h), rena l fun c tion im pairm ent (c re -a t in ine > 1 .0 m g/d l), o r h yperur icem ia . D eve lopm ent of theseor o ther co m plica tions is an ind ica tion for de live ry , esp ec ia llyw hen pregnancy is a t o r beyo nd 32 w eeks o f g es tatio n . M od-era te h ypertension (d iasto lic b lood pressure 95 to I 00 m m H g)shou ld lead to th e use o f an y o ne of severa l su itab le an tihy-pertens ive ag en ts if d e live ry is no t d esirab le because o f p re -m aturity (T ab le 3 ).

M ethy ld opa h as b een u sed ex tensive ly in p regn an cy an d iso ften th e agen t o f f irs t cho ice . A lth oug h th is agen t has beenla rge ly abandon ed fo r g enera l u se in essen tial hyp er tens ionbecause of the side effec ts o f o rthos ta tic hypo tens ion andfa tigue , m ethy ldopa is bo th sa fe an d effec tive in preg nancy . Ina tria l o f m ethy ldopa versus p laceb o to trea t hy pe rten sion inpregn an cy by R ed m an e t a l. , m eth y ldopa effec tiv ely con tro lledb lood pressure (15 ). M ethy ld opa therapy a lso y ielded b e tte rfe ta l ou tco m e (few er m id -p regn ancy abo rtion s), bu t had n oeffec t in preven ting preeclam psia. A n in itia l co ncern w as tha tin fan ts born to m others w ho h ad rece ived m ethy ldop a hadsm a ller head circum fe rence fo r g es tatio na l age . W h en th esein fan ts w ere eva lua ted a t 1 year, a ll h ead s izes w ere norm al 1 6). M ore im portan tly , in fan ts born to w om en w h o h ad re -ce iv ed p lacebo scored w orse o n the D env er D eve lopm enta lScreen ing T es t than d id in fan ts w hose m others rece ived ac tive


5/8

3 8 Journa l of the A m erican S oc ie ty of N ephro logy

Tab le 3 . A ntihypertens ive ag en ts in pregn an cyF irst cho ice

m ethy ldopaa ten obo l, m etop ro bo llabetabo lhydralazinehydrochboro th iazidea

A lso usefu lcbon id inen ifed ip ineisradipineprazos i n

Contraind icatedang io tens in -converti n g enzym e inh ib ito rsang io tens in recep to r b lo ck ers

P aren te ra l agen ts fo r seve re hy pe rtens ionhydralazinelabetalo lm agnesiu m su lfa tes od iu m n itro pr us sid eaa S ee tex t fo r specif ic g u ide line s.

the rapy (m e thy ld opa ) . T h ese in fan ts w ere eva lua ted aga in at 4years of ag e ( I 7). In d ev e lo pm enta l tes ts . the m ean sco re fo rtre a ted ch ild ren w as co nsisten tly h ighe r th an fo r ch ild renw h ose m o the rs rece ived p laceb o . T h e au tho rs su ggested th atm a terna l h ype rten sion is a sso cia ted w ith m ild deve lo pm en ta lde lays in early ch ildho od and th a t m eth y ldopa reduced th isad ve rse e ffec t o f hy pe rtens ion in p regn an cy . O the r stud ieshave no t so in tens ive ly ev alu ated lo ng-term fe tal ou tco m e , b u thave focused on m ate rna l and fe ta l hea lth during and im m e-d ia te ly a fte r p reg nancy .

B eta-ad ren erg ic b locke rs a re use fu l alte rna tive s to m e thy l-do pa . A teno bo l and m eto p ro lo l a re the b eta -b locke rs fo r w h ichthe re is the large st bo dy of ex pe rience and the g rea te st en thu -siasm for use in pregnancy . T he com bined a lph a- and b eta -b locke r labe tabo l h as a lso been used frequen tly . D esp ite con -cerns abo u t be ta -b lo cke r- indu ced fe tal b radyca rd ia, th iscom p lica tion has no t b een d etec ted in m o st stu d ie s . S eve ra lstud ies us in g be ta -b lockers have no ted decreases in b irthw eigh t com pared w ith in fan ts w ho se m others rece ived p la -cebo . A n eq ua l num b er of s tud ies have fa iled to f in d any effec tof be ta -b locke rs o n fe ta l deve lo pm en t. R ub in an d co lleag uesshow ed tha t a ten obo l redu ced pe rin ata l m orta lity w h en used totrea t h ype rten sion tha t d ev e loped in th e th ird tr im este r ( 1 8). O nthe o th er h and , th is s am e grou p fou nd tha t a teno lo l w as asso -c iated w ith in trau te rine gro w th re ta rda tio n (low er b ir th w eigh tsan d low er p lacen tal w e igh ts) w h en in itia ted a t the en d o f thefirst trim este r in w o m en w ith chron ic hypertens ion ( I 9). F ro mthe se stud ies , it is d ifficu lt to k now w he the r the d iffe rences inou tco m e a re re la ted so le ly to the tim ing o f an tihy pe rtensiv e use 1 st versus 3rd tr im ester) o r w h eth e r the na tu re and chron icityo f the hyp ertension exp la in the se d ive rg en t resu lts . B ecause o fth is uncerta in ty . phys ic ian s trea tin g hypertens ive w om en have

o ften proceed ed cau tious ly in the app lica tion of an tihyperten -s ive drugs .

C en tra lly ac ting adren erg ic agen ts such as c lon id ine , thea lph a-ad renerg ic an tago n ist p razo sin . and d ihyd ropyr id in e cab-c ium -ch an ne l b lo ckers such as n ifed ip ine have a lso been suc-cessfu lly u sed to trea t m odera te hy perten sion in pregn ancy .P heny la lky lam ine and benzo th iazep ine ca lc iu m -channe lb lo ckers (v erap am il and d iltiaze rn ) , un like d ihydropyrid ines ,m ay s low lab or and sh ou ld be av o ided in the im m edia te prepar-tu rn period . F or m o re sev ere hyp erten sion . com bina tions o fag en ts can be used . F or exam ple , h ydra laz in e. w h ich a lso hasa long h is to ry o f sa fe use in pregnancy , can b e added to any o fthese agen ts .

D iure tics are ad ju nc ts in the trea tm ent o f p reec lam psia b e-cause the fund am enta l p atho phys io log ic abnorm ality is n o tso d ium reten tio n b u t vaso co nstr ic tion . A t on e tim e , th iaz ide sw ere adm in is te red proph y lactica lly to prev en t p reeclam psia. Anie ta -ana lysis sug gested tha t th iaz ide d iu re tics w ere effec tiv efo r th is purpo se . bu t th is p ractice has been appropria tely aban -d oned b ecause th e e ffect w as sm a ll and fea rs o f causing vo l-u m e d ep letio n in v asocons tric ted w om en w ere g rea t (2 0 ) .N everthe less, th a t experience sugges ts tha t th iazides can b eused safe ly du rin g pregnan cy w hen vo lum e excess is p resen t o rw hen com b in a tion an tihy perten sive th erap y is requ ired .

W hen preec lam psia is seve re , rena l sod iu m reten tio n do esd eve lo p as a resu lt o f im pa ired rena l b lood flow and d ecreasedG F R . In the se w om en , edem a b eco m es m ore p rob lem a tic andp u lm onary edem a can becom e a life -th rea ten ing co m plica tion .In p reecb am psia , pu lm ona ry cap illa ry w ed ge pressu re is ele -v a ted in app rox im ate ly one-th ird o f th e w o m en stud ied . T h em ajority of w om en w ith pu lm onary edem a h av e e leva ted pu l-m onary cap illa ry w ed ge p re ssu re . T he refo re , it is app ro p riateto use d iu re tics in p atien ts w ho h av e sy m ptom s of co nges tiveheart fa ilu re o r vo lum e excess .

Severe hyp er tens ion (d ias to lic b lood pressure > 100 m m H g)req u ires urg en t trea tm ent. O f the paren te ra l an tihypertens iveag en ts ava ilab le , hydra laz ine and labe ta lo l a re m o st frequen tlyused . H y dra laz ine has re flux tachycard ia as a m ajor s ide effec t,w hich m ay lim it its e ffec tiveness : add ition of a b e ta -b lo ck erred uces th e severity of th is p rob lem . O ra l n ifed ip ine has b eensuccessfu lly u sed w hen p aren te rab agen ts w ere no t con ven ien t.T he m o st seve re h ype rten sion can be treated w ith so d iumn itrop russ ide in fusion if de live ry is im m in en t. S od ium n itro -p russide w ill e ffec tive ly lo w er b lo od pressure and can b eaccura te ly titra ted . B ecause of the r isk o f fe ta l cyan ide tox ic ity ,sod ium nitropru ss id e is rese rved for hypertens iv e em erg en ciesand is u sed for less than a few ho urs . M agnes iu m su lfa te hasw eak an tih ypertensive effec ts tha t a re o f b en ef it in severepreec lam psia . M ore im portan tly , m agnesiu m su lfa te p reven tsse izures in preec lam ptic w om en and has been foun d to b esu pe rio r to ph en y to in fo r tha t pu rpo se . A s a lterna tive s fo rse izure prev en tion and trea tm en t, pheny to in and d iazepam canb e u sed . B ecause hy pe rm ag nesem ia re su lts in re sp ira to ry p a-ra lys is, m agnes ium su lfa te m u st be ad m in iste red care fu lly . T h ed ose of con tinu ous in fu sions m ust be reduced in w o m en w ithim paired rena l fu nc tio n . M uscu la r and resp ira to ry para lys is istrea ted w ith in trav enou s ca lciu m .


6/8

P regnancy : A R isky B usiness 31 9

OutcomeP reec lam ps ia is as soc ia ted w ith an in crease in pe rina tal

m o rb id ity an d m orta lity . A m a jo r featu re o f p reec lam psia isdecreased u te rop lacen ta l b lood flo w b ecause of v asocons tric -tion . P a tho lo g ic ch anges a re m os t ap pa ren t in th e sp ira l a r ter ie so f the p lacen ta , a conseq uence o f im p aired p rostag land in p ro -du c tio n by trop hob la sts . Im p aired u te rop lacen ta l p erfusionlead s to in trau ter ine g ro w th re tarda tion . F e tuses a re a lso a t r iskin p reec lam psia because o f an in creased inc idence o f ab rup tiop lacen ta.

W o m en w ho deve lop p reec lam psia in a f irs t p reg nancy b u tw h o are n orm otens ive in su bsequ en t p reg nanc ie s hav e n olong -te rm m orb id ity o r m orta lity re lated to th e in itia l ep iso deof p reec lam psia . E p id em io log ic stud ies have fou nd th a t the sew o m en have n o inc rea sed p reva lence o f hyp ertensio n an d havea norm a l life ex pec tan cy . In m ark ed co n tra st, w o m en w hodeve lop preec lam psia in a secon d pregnan cy o r in m u ltip lep reg nanc ie s h av e an in creased p reva lence o f h ype rten sion an dgrea te r m orta lity than ag e-m a tched con tro l sub jec ts . W henw o m en w ith m ultip le ep iso des o f p reec lam psia w ere eva lua ted20 to 40 y ears af te r th eir in itial p regnancy , the preva lence ofhypertens io n w as approx im ate ly tw ice tha t o f the con tro l po p-u la tion . H yp ertension is be lieved to be the cause o f th e ex cessv ascu lar d isea se and p rem a tu re dea th in such w om en . T h isobse rva tion is con sisten t w ith our cu rren t un de rstan d ing ofp reeclam p sia . Id iopa th ic o r p rim ary p reec lam psia is a d is-ease th at occu rs in nu llipa rous w om en . M ajor risk fac to rs fo rrecu rren t o r second ary p reec lam psia a re ch ron ic h ype rten -sion , rena l d isea se, an d d iabe te s . T h ese d isea se s pe rsis t lo nga fter p regn ancy has en ded , and the ir a sso cia ted m o rb id ity andm o rta lity acc ru es . W hen p reec lam psia o ccu rs in the f irs t ha lf o fp regn an cy , it is m o re lik ely to be second ary to on e of th esed iseases (21 ,22 ). F or such w om en , the re a re long -term hea lthrisk s. W om en w ho d ev elop preec lam psia la te in a first p reg-nancy and w h o hav e no ev idence o f hy pe rtensio n o r rena ld isease be tw een and dur in g sub sequen t p regnanc ies can berea ssu red o f a fav orab le lo ng-te rm o u tcom e .

H yperten sion C om plica ting R ena l D iseaseDiagnos i s

R en al d isease is one m an ife sta tion o f p reec lam psia . O n theo th er hand , rena l d isea se p red ispo se s to the d ev elo pm en t o fsup erim p osed preec lam ps ia. T h is d istin ctio n is m ade m o red ifficu lt if a w om an has no t b een ev alu ated be fo re p regn an cyor ea rly in gesta tion . E v en sub tle rena l d isea se m ay pred isp oseto the deve lop m en t o f p reec lam p sia. F o r ex am ple , w o m en w itha h isto ry o f re f lux du rin g ch ild hoo d bu t w ith n orm a l rena lfu nc tion have an inc rea sed inc idence o f p reeclam p sia an dpe rin ata l co m plica tions . U rin a ry ab no rm a litie s in the firs t tn -m este r shou ld sugges t und erly in g rena l d isease . A lthough thefractio na l exc retio n o f alb um in in creases d u ring p regn an cy ,p ro te in ex cre tio n is usua lly n o t g reate r th an 250 m g/2 4 h .P ro tein exc re tion in exces s o f th is am oun t can b e caused b yeith er in tr in sic rena l d isease o r p reec lam ps ia. H em atu n ia is no ta usua l find ing in preec lam p sia and sug gests g lo m erubon ep hri-tis . T ab le 2 ou tlines those find ings tha t he lp to d iffe ren tia te

p reec lam p sia from chron ic hy perten sion or h ypertensio n asso-c ia ted w ith rena l d isease .

Pregna ncy O utcom eF e tal lo ss , in trau te r ine g ro w th re ta rda tion , and p rem a tu rity

are the m ajor fe ta l consequences o f m aterna l rena l d isease . T h em o st im portan t risk fac to r fo r these u ndesirab le fe tal ou tcom esis hyp er tens ion , a lthough rena l insuffic iency and h igh -gradep ro te in un ia a lso po rten d a less favorab le o u tcom e. W ith severeh ype rten sion (> 175 /1 10 m m H g). fe tal lo ss ra te s g rea ter than6 0% have been repo rted . T he risk of deve lop ing su perim posedp reeclam p sia d u ring p regn an cy in w om en w ith rena l d is ea sevaries be tw een 20 and 40% . F or th is reaso n , it seem s reason-ab le to beg in low -dose asp irin early in preg nancy in w om enw ith rena l d isease in ex pec ta tion of p rev en tin g preec lam psia .

R ena l O u tcom e: T es ting th e H vp eifiltra tion H ypo thesisP regnancy is a po ten tia l te st o f th e h yp erfiltra tion h ypo the -

sis , o rig ina lly a rticu la ted by H oste tte r, B renner, and co l-leag ues, p ropo sing tha t an increase in g lo m eru la r cap illa ryhyd ros ta tic p ressu re is a cen tral facto r in the inexo rab le p ro-g ression of chron ic rena l d iseases . P reg nancy m igh t be partic -u la r ly risk y in th is reg ard because rena l va sod ilatio n is ch ar-ac ten is tic o f p regnancy . In th e p resence of sys tem ichypertens ion , a grea te r portion of sys tem ic b loo d pressurew o uld be tran sm itted in to the g lom eru lus , po ten tia lly exacer-ba tin g in ju ry . T o tes t th is hypo th es is, one w ould first need toascerta in w hether p regn an cy resu lts in an irreversib le de ten io -ra tion in rena l fun c tion in w om en w ith ch ro n ic rena l in su ff i-c ien cy . A ltho ugh the gen eral answ er to tha t q uestion is yesw ith the fo llow ing pro v isos , it has no t been possib le to s tudym ech an ism s of in ju ry in w om en . P regnan t ra ts h av e beenstud ied , bu t m ay no t be a su itab le m ode l fo r the hum an expe-n ience . Fo r exam ple , the sp on taneous ly hy perten sive ra t d oesno t d ev elo p the exp ec ted a fferen t a rte rio lar va sod ila ta tion o fpregnancy , does n o t exp er ience th e usu a l p regnan cy -inducedincrease in G FR , and a lso d oes no t d eve lo p in creased in trag lo -m eru la r p re ssu re during pregnancy o r p rog re ssive rena l failu re .O n th e o th er hand , in expe rim en ta l gb om eru lon ep hn itis p ro -duced b y in jec ting ra ts w ith A d riam y cin , sy stem ic hyp erten -s io n d id exacerba te pro te inuria . po ss ib ly in d icating irrevers ib lerena l in ju ry .

W om en w ith rena l d is ea se w ho h av e n orm a l G F R , n orm a lb loo d pre ssu re , and no p ro te in un ia do no t su ffe r rena l im pa ir-m en t du ring p regn an cy . In con tras t, ap p rox im a te ly o ne -th ird o fw om en w ho have rena l in su ffic iency w h en they b eco m e preg -n an t su ffer an irreve rsib le , acce lera ted de te rio ra tion in rena lfu nc tion (23 ,24). H y perten sion h as o ften been found to be anadd itiona l risk facto r fo r th is de te rio ra tio n dur in g preg nancy .Th e hy perfiltra tion hy po thesis has n o t been fu lly tested , how -ever, because there has been n o adequa te dem o nstra tion (orlack thereof) tha t agg ress iv ely trea tin g hyp er tens ion to prev en tin trag lom eru la r hyp ertension n ecessa rily p reven ts irrev ersib led ete rio ra tion o f rena l func tio n during p regn an cy in the se h igh -risk w om en .


7/8

32 0 Jou rna l o f the A m erican S oc ie ty o f N ephro lo gy

M anag em en tC urren t p rac tic e is to con tin ue an tihy pe rtens ive th erapy

w hen pregnancy dev elo ps, bu t the ex ac t g oa l fo r b lo od pres -su re co n tro l h as n o t b een estab lish ed . T oo low m ate rn a l b loodpre ssu re po ten tia lly pu ts the fe tus at r isk , w he rea s to o h ighb lo od p re ssu re en dang ers bo th m oth er an d ch ild . A s no tedabo ve , th e re is a w ide rang e of an tihy pe rtensiv e ag en ts tha t canbe sa fe ly u sed during p regn ancy . A n im portan t excep tion to th erule of con tinu in g curren t th erapy w h en pregnancy d ev elo ps isthe u se o f ang io ten sin -co nve rting enzym e inh ib ito rs (A C E I) .A C E have b een asso cia ted w ith inc rea sed fe ta l lo ss in exp er-im en ta l an im a ls an d w ith feta l ren al tu bu la r d ysp la sia , p er ina ta lacu te ren a l failu re , an d o the r cong en ita l anom alie s . T h e m o th -e rs o f the se unfo rtuna te in fan ts have a ll con sum ed A C E in thesecond o r th ird tr im este r o f p regn ancy , o r b o th . A recen tp ost-m ark etin g su rvey of A C E in th e U n ited S tate s , C anada ,and Israe l revea led n o ad ve rse fe ta l o u tcom es because o f use o fA C E in the firs t tr im este r on ly (25 ). T he refo re , w h en w om enrece iv in g A C E beco m e p regn an t, they sh ou ld be sw itch ed too the r an tih ype rten sive agen ts . H ow eve r, w hen ex posu re islim ited to the f irs t trim este r , it do es n o t appea r necessa ry toin ten tiona lly te rm in a te the p regnan cy . O n e m us t a ssum e tha tang io tensin I re cep to r b locke rs a re sim ilar ly con tra ind ica tedfo r use during pregnan cy . A ng io ten sin type 2 (A T 2) recep to rsa re invo lved in deve lop m en t o f the feta l k idney . It is no t c lea rw he the r b lock in g on ly type 1 recep to rs (A T ,) w ou ld also pu tth e fe tus a t r isk , bu t w ith the la rg e nu m ber o f accep tab lea l te rna t ives the se ag en ts sho u ld no t be used .

C hron ic H yp erten sionEssen tia l H ypertensio n

E ssen tial hyp ertension is a m ajo r r isk fac to r fo r th e deve l-opm en t o f sup erim p osed preec lam psia . S om e w o m en w ithes sen tia l h ype rten sion fail to have the d ecrease in b lo od pre s-su re tha t is a m an ife sta tion o f vasod ilata tion in ea rly p reg -nancy . W h en b loo d pressu re d ete rm ina tion s be fo re p reg nancya re no t ava ilab le , the ea rly lack of a d ec rea se in b loo d pre ssu rew ill be m issed and the d iagno sis o f ch ron ic hy pe rtensio nso m e tim es m ay no t be ce rta in un til p ostpa r tum fo llo w -up .H yp ertensio n d ue to p reec lam psia re so lv es w ith in 7 day s a f terde live ry . S om e w om en w ith e ssen tia l h ype rten sion w ill h av ere so lu tion o f h ype rten sion im m ed ia tely a fte r d eliv ery b u t w illdeve lop h ype rten sion in la te r y ea rs o r du ring a sub seq uen tp reg nancy . T ab le 2 h igh lig h ts the clin ica l featu re s o f hy pe r-ten sive d iso rde rs and dem o nstrate s ho w essen tia l hyp ertensioncan som e tim es be d iffe ren tia ted from th e o th e r cau se s o f hy -pertension in p regnancy .

W om en a lready receiv ing an tihy pe rtens ive th erapy a re u su -ally con tinued on the ir m ed ica tio n d urin g pregnancy . T h isin clu des con tinua tio n of a d iu retic w hen it is par t of the usua lreg im en . A C E and an g io tensin I recep to r b lo cke rs shou ld b ed iscon tinued as soo n as p regn an cy is reco gn ized . T he d ev el-opm en t o f m ild h yp ertension , ev en ea rly in p regnan cy , p resen tsa m ore co n trove rsial issue . S m all elev atio ns in b lo od pre ssu reare no t lik ely to be ha rm fu l to m oth er o r fetu s. H ow eve r, m oreseve re eleva tion s in b lood pres su re a re r isky to bo th th e m othe ran d fetu s. M a terna l r isks a re large ly re lated to ce reb ra l hem -

orrh ag e. F e ta l r isks in c lude in trau te r ine g row th re tarda tion anddea th . M ost p rac tition ers w ou ld ag ree w ith s tar ting an tihyp er-tensive the rapy w h en d ia sto lic b lo od pre ssu re exceed s 1 00m m H g . B ecause fe tal m o rta lity is inc rea sed w hen b lood p re s-su re ex ceeds 85 to 90 m m H g, som e w ould argue fo r th ein itia tion o f an tihy pe rtensiv e the rap y at th ese lev e ls o f b lo odpre ssu re . H o w eve r , p ro spec tiv e , rando m ized , con tro lled tr ialshav e n o t con sisten tly d em on stra ted m a te rn al o r fe ta l bene fit fo rtrea tm en t o f m ild h yp erten sion in p regn an cy (14 ,2 6 ) . M anyep id em io log ists have a rgu ed th at the reported stud ies h avebeen too sm a ll to dem onstra te sm a ll bene fic ia l effec ts o f an ti-hy pe rten sive th erapy . H o w eve r , m an y stud ie s a re a lso to osm a ll to d em onstra te p ossib le in frequ en t d e tr im en ta l effec ts o ftoo ag gre ss ive an tihyp ertensive the rap y . T he read er sh ou ld berem inded th at the deba te cen te rs m ostly o n th erapy of m ildhy pe rten sion . E xp e rts n ow recom m end th e u se o f an tihyp e r-tensiv e the rap y fo r m o de ra te ly seve re h ype rten sion com plica t-ing p regn ancy (2 7 ) .

S eco nda ry H yp erten sionS econd ary cau ses o f hy pe rtens ion occas iona lly p re sen t in -

te re stin g p ro b lem s in p reg nancy . P rog este rone h as the capab il-ity o f an tago n iz in g the ka liu re tic ef fect o f m inera locortico ids .In w om en w ith hyp era ldoste ron ism , the an tagon ism of m ine r-a loco rtico ids by prog este rone d uring p regn an cy is va riab le .S om e w o m en w ith p rim ary hy pe ra ldo ste ro n ism have rev ersa lo f p o ta ssiu m w asting an d le ss hyp er tens ion du ring pregn an cy .In o the rs , h ype rten sion d ue to so d ium reten tio n is exace rba tedb y p reg nancy and occasiona lly resu lts in severe hypertens ion .

Ph eochrom o cy tom a is no tab le fo r its ab ility on ra re occa -sio ns to h av e a d ram a tic p resen ta tio n d uring preg nancy w ithfata l o r nea r-fa ta l co m plica tion s. U n recogn ized , m a te rn a l andfe tal m o rta lity in ph eo ch ro m ocy to m a approaches 25% . W ithapp rop ria te u se o f a iph a-ad ren erg ic b locke rs , m a te rn a l m ortal-ity can be prev en ted , a lthou gh som e risk to the fe tus pe rs is ts .

References1 . G rim es D A : T he m o rb id ity and m orta lity of p regnancy : S till

risk y b usin es s. Am J O bs tet G yn eco l 170 : 1489 -1494 , 199 42 . Sch iff E , P e leg E , G oldenberg M , R osen tha l T , R up pin E , T a-

m akin M , B arka i 0 , B en-B aruch G , Y aha l I, B lanks tein J,G oldm an B , M ash iach 5 : T he u se o f a sp ir in to p rev en t p regnan-cy-indu ced hypertens io n and low er the ra tio o f th rom box an e A 2to pros tacyc lin in rela tive ly h igh risk pregn an cies . N EngI J M ed3 2: 3 51 3 56 1 98 9

3 . U zan 5 , B eaufils M , B rea t G , B az in B , C ap itan t C , P aris I:P rev en tio n of fe ta l g row th reta rda tion w ith low -do se asp ir in :F in d ings o f the E PR E D A tria l. Lance t 337 : 1427 -143 1 , 1 991

4 . B eaufils M , U zan 5 , D on sim oni R , C olau IC : P reven tion o fpre -ec lam psia by early an tip la te le t th e rapy . Lan ce t i: 840-8 42 ,1985

5 . Im peria le T F , P etru lis A S : A m eta -ana lys is o f lo w -d ose asp irinfo r the p rev en tion o f p reg nancy-indu ced hyp e rtensiv e d isease.JAMA 2 66 : 260-264 , 19 91

6 . S iba i B M , C aritis S N , T hom E , K leb anoff M , M cN ellis D , R occoL, P au l R H , R o m ero R , W itte r F , R osen M , D epp R : P reven tio nof preec lam psia w ith low -dose asp irin in h ea lthy , nu llipa rou sp re gn an t w om en . N Engl J Med 329 : 1213 121 8 1993


8/8

Preg nancy : A R isky B usiness 321

7 . C ollab ora tiv e L ow D ose A sp irin S tud y in P regnancy (C L A SP )C o llab o ra tive G ro up : C L A S P : A rando m ised trial o f low -doseasp ir in fo r the prev en tion an d trea tm ent o f p re -ec lam p sia am on g936 4 pregnan t w om en . Lance t 343 : 619-6 29 , 1994

8 . E C P PA C ollaborative G roup : E C PP A : R ando m ised tr ia l o f lo wdose asp irin fo r the preven tion o f m ate rna l and feta l com p lica -tio ns in h igh risk pregnan t w om en . B r J O bs tet G ynaeco l 103 :39 47 1996

9 . S iba i B M , C aritis SN , T ho m E , Shaw K , M cN ellis D : L ow -doseasp irin in nu llipa rous w om en: S afe ty of con tinuou s ep idura lb lock and corre la tion be tw een b leed ing tim e and m aterna l-neo-na tal b leed in g com p lica tio ns. N atio na l Institu te o f C h ild H ea lthan d H u m an D eve lop m en ta l M a terna l-F eta l M ed icin e N e tw ork .m J Obstet Gynecol 1 7 2: 1 5 53 1 5 57 1 9 95

10 . C L A SP C ollabora tive G rou p : Lo w dose asp irin in pregn ancy andearly ch ildhoo d deve lop m en t: F o llow -up of th e C ollab ora tiv eL ow D ose A sp ir in S tudy in Pregnan cy . Br J O bs te t G yna eco l1 0 2: 8 6 1 8 6 8 1 9 95

1 1. B elizan JM , V illa r I , G on za lez L , C am pod on ico L , B e rge l E :C alc ium su pp lem en ta tion to p reven t hyp e rtensio n d iso rde rs o fpregnancy. N Engi J Med 3 25 : 1 39 9 1 40 5 1 99 1

12 . B ucher H C , G uya tt G H , C oo k R I, H ata la R , C ook D I, L ang ID ,H u nt D : E ffec t o f ca lc ium su pp lem en tatio n on pregnancy -in -duced hy perten sion and preec lam p sia : A m eta-an a ly sis o f ran-dom ized co n tro lled tr ials . JAMA 275: 1 1 1 3 1 1 17 1 996

13 . L ev ine R J , H au th IC , C u re t LB . S ib a i B M , C ata lano PM , M o rrisC D , D erS im on ian R , E ste r litz JR . R aym ond E G , B ild D E , C le -m ens JD , C utle r IA : T ria l o f ca lc iu m to p reven t p reec lam psia .N Engl J Med 3 37 : 6 9 7 6 1 99 7

14 . Ph ipp ard A F , F ischer W E , H orva th IS , C hild A G , K orda A R ,H ende rson -S m art D , D ugg in G G , T ille r D I: E a rly b lo od pre ssu reco n tro l im p rov es p reg nancy ou tco m e in p rim ig rav ida w o m enw ith m ild hy perten sion . MedfAus t 1 54 : 3 7 8 3 8 2 1 9 91

15 . R ed m an C W G , B eilin L I, B on nar I, O u nsted M K : F e ta l ou tcom ein tria l o f an tihyp er tens ive treatm ent in pregn an cy . L ance t ii:753 756 1976

16 . M utch L M M , M oar V A , O un sted M K , R ed m an C W G : H yp er-tens io n during p regnancy , w ith and w itho u t sp ecific hypo ten sive

trea tm ent. II . T he grow th an d deve lopm ent of the in fan t in th efirs t year o f life . Ear ly H um D ev 1 : 59 -67 , 1 977

17 . O un sted M K , M oar V A , G ood F l, R edm an C W G : H y perten sionduring preg nancy , w ith and w itho u t sp ec if ic hyp o tensiv e treat-m ent: T he deve lopm ent of the ch ild ren a t the ag e of four years.B r J O bste t G ynaeco l 87 : 19 -24 , 19 80

18 . R ubin P C , B utte rs L , C la rk D M , R eynolds B , Su m ner D I,S teedm an D , L ow R A , R e id IL : P lacebo -con tro lled tr ia l o fa teno lo l in treatm en t o f p regnancy-a ssoc ia ted hyp ertension . Lan-ce t I: 431 -434 , 19 83

19 . B u tters L , K enn edy S . R u b in P C : A ten o lo l in e ssen tia l h ype r-tens io n d uring pregn ancy . B r M ed J 30 1 : 58 7-589 , 1 990

2 0 . C ollins R , Y usuf 5 , P e to R : O verv iew of rand om ised tr ia ls o fd iu retics in pregnancy . B r M ed J 290 : 1 7-23 , 1 985

2 1 . Ih le B U , L ong P . O ats I: Early o nse t p re -ec lam psia : R ecog n itionof un derly ing ren a l d isease . B r M ed J 294 : 79- 8 1 , 1987

2 2 . R eite r L , B row n M A , W hitw o rth IA : H ypertension in preg nancy :T he inc idence of und erly ing rena l d isease an d essen tia l hy per-tension. m J Kidney is 2 4 : 8 8 3 8 8 7 1 9 94

23 . H ou S H , G rossm an S D , M ad ias N E : Pregn an cy in w om en w ithrena l d isease an d m o dera te rena l insuffic iency . Am J M ed 78 :185 194 1985

24 . lones D C , H ay sle tt IP : O utcom e o f pregnan cy in w o m en w ithm odera te or severe rena l in sufficiency . N Eng l J M ed 335:226 232 1996

25 . M M W R : P os tm arke tin g su rve illan ce fo r a ng io ten sin -co nve rtingenzym e in h ib ito r u se during the firs t trim es te r o f p regn ancy :U n ited S ta tes , C anada , and Israe l, 1987 -1995 . M orb M orta lW eek ly R ep 46 : 2 40-24 2 , 1997

26 . S iba i B M , M abie B C , Sh am sa F , V ib la r M A , A n derso n G D : Acom pariso n o f no m edica tio n versu s m ethy ldo pa o r labe talob inchron ic hypertens ion dur in g pregnancy . Am J Ob ste t G yn eco l1 6 2: 9 6 0 9 6 6 1 9 90

27 . C om m ittee on T ech n ical B ulle tins of th e A m erican C ollege o fO b ste tric ians and G yneco log ists : A C O G tech n ical b u lle tin : H y-p er ten sion in p regnancy (N um b er 21 9 , January 1 996). m t JG ynaeco l O bste t 5 3: 1 75 1 83 1 99 6

Documents

DISEASE OF THE MONTH314.full