Caffeine intake and pregnancy outcomes:
a meta-analytic review
Co nsumo d e c afe ína na g ravid e z
e d e sfe c ho s p e rinatais
1 Program a d e Pós- Gra d u a çã o em Ep id em iologia , Un iv ersid a d e Fed era l d e Pelot a s, Ca ix a Post a l 464, Pelot a s, RS 96100- 970. Bra z il.
2 Departm en t of Epidem iology a n d Pop u la t ion Scien ces, Lon d on Sch ool of Hygien e a n d Trop ica l M ed icin e, Kep p el St reet , Lon d on W C1E 7H T, U K.
In á S. Sa n t os 1
Cesa r Gom es Vict ora 1
Sh a ron Hu t t ly 2
Sa u l M orris 2
Abst ract Ep id em iologica l p u b lica t ion s on t h e rela t ion sh ip of ca ffein e t o b irt h w eigh t a n d d u
-ra t ion of h u m a n p regn a n cy, from 1966 t o 1995, w ere sea rch ed t h rou gh M ed lin e. Ea ch st u d y w a s t rea t ed a s t h e st ra t ifica t ion va ria ble, a n d it s w eigh t in t h e w eigh t ed a vera ge w a s p rop ort ion a l t o t h e in v erse of it s v a ria n ce. Tw en t y- six st u d ies w ere loca t ed . Am on g t h e t w en t y- t w o st u d ies on birt h w eigh t , eleven w ere on m ean birt h w eigh t , n in e on low birt h w eigh t (LBW ), an d fou r on in -t ra u -t eri n e grow -t h re-t a rd a -t i o n (IU GR). Co m b i n ed a n a lysi s o f m ea n b i r-t h w ei gh s-t u d y resu l-t s sh ow ed a sign ifica n t d ecrea se in birt h w eigh t of n ea rly 43g a m on g n ew born s of t h e h ea v iest ca f-fein e- con su m in g m ot h ers. LBW, IU GR, a n d p ret erm d eliv ery d isp la yed sign ifica n t h om ogen eit y in t h e t est resu lt s, in d ica t in g t h a t a p ooled est im a t e sh ou ld n ot b e t a k en a s a n a d eq u a t e m ea-su re. T h e h igh h et erogen eit y of t h e a v a ila b le lit era t u re on t h e effect s of ca ffein e on LBW, IU GR, a n d p ret erm d eliv ery p rev en t s est im a t ion of relia b le p ooled est im a t es t h rou gh m et a - a n a lysis. Fu rt h er assessm en t of caffein e in t ak e d u rin g p regn an cy is n eed ed in fu t u re research .
Key words Caffein e; Low Birt h Weigh t ; Fet al Grow t h Ret ard at ion ; Prem at u re In fan t
Resumo Fora m ra st rea d a s a s p u b lica ções ep id em iológica s d e 1966 a 1995 sob re a a ssocia çã o
en t re ca feín a e p eso a o n a scer e d u ra çã o d a gest a çã o h u m a n a a t ra v és d e p esq u isa em M ed lin e. Ca d a est u d o foi t ra t a d o com o u m a ca t egoria d e u m a v a riá v el e seu p eso foi p rop orcion a l a o in -verso d e su a va riâ n cia . Fora m loca liz a d os v in t e e seis est u d os. En t re os v in t e e d ois est u d os sobre p eso a o n a scer, on z e fora m sob re p eso m éd io a o n a scer, n ov e sob re b a ix o p eso a o n a scer (BPN ) e q u a t ro sob re ret a rd o d o crescim en t o in t ra - u t erin o (RCIU ). O efeit o a grega d o sob re o p eso m éd io a o n a scer m ost rou u m a red u çã o est a t ist ica m en t e sign ifica t iv a d e 43 gra m a s en t re os recém -n a s-cid os d e m ã es q u e con su m ia m m a iores q u a n t id a d es d e ca feín a . A a n á lise a grega d a d o efeit o so-b re BPN , RCIU e n a scim en t os p ré- t erm os a p resen t ou t est e d e h om egen eid a d e est a t ist ica m en t e sign ifica t ivo, in d ica n d o q u e u m a est im a t iva com b in a d a n ã o seria con fiá vel. A gra n d e h et eroge-n eid ad e d a lit erat u ra d isp oeroge-n ív el qu aeroge-n t o ao efeit o d a cafeíeroge-n a sobre o BPN , RCIU e p art os p ré-t er-m o n ã o p erer-m it e o cá lcu lo con fiá vel d e est ier-m a t iva s a gru p a d a s a t ra v és d e er-m et a - a n á lise. Torn a - se n ecessá ria u m a a v a lia çã o m a is cu id a d osa d o con su m o d e ca feín a d u ra n t e a gest a çã o em est u -d os fu t u ros.
Introduction
Th e e ffe ct o f ca ffe in e co n su m p tio n o n b ir th weigh t an d d u ration of p regn an cy h as b een th e su b je ct o f n u m e ro u s e p id e m io lo gica l stu d ie s in re ce n t ye a rs. Ma jo r so u rce s o f ca ffe in e a re co ffee, b la ck tea , m a té, ch o co la te/ co co a , a n d cola soft d rin ks. It h as also b een estim ated th at n early 200 n on -p rescrip tion d ru gs con tain caf-fein e, an d th is m ay b e an im p ortan t sou rce for a m in ority of p eop le.
Caffein e (1,3,7-trim eth ylxan th in e) is a p lan t a lka lo id , stru ctu ra lly rela ted to DNA p u rin e b ases, th e focu s of stu d ies with lab oratory an i-m a ls. Ca ffein e is a p h a ri-m a co lo gica lly a ctive su b stan ce with effects on m an y d ifferen t organ system s. In terest in th e stu d y of caffein e on h u -m a n p re gn a n cy, h owe ver, is b a sed o n th e fa ct th at its clearan ce is delayed in p regn an t wom en , m a in ly in th e se co n d a n d th ird trim e ste rs, wh en it is d ecrea sed to o n e h a lf a n d o n e th ird th e n o rm a l ra te, re sp e ctive ly (Ald rid ge e t a l., 1979). Caffein e crosses th e p lacen tal b arrier so th at m atern al an d fetal b lood levels are virtu ally th e sam e (Gold stein & Warren , 1962). Th e en zym es n eed ed for caffein e m etab olism are ab -se n t b o th in th e fe tu s a n d u n til th e e igh th m o n th a fte r d e live r y (Ho rn u n g e t a l., 1985 a p u d Ja m es & Pa u ll, 1985). Con cern a b ou t th e p o ssib le h a rm fu l e ffe cts o f ca ffe in e o n p re g-n ag-n cy h as evolved m aig-n ly from stu d ies ig-n ag-n im a ls th a t h a ve in d ica te d a d e cre a se in in -tra u terin e feta l growth , red u ced b irth weigh t, a n d skeleta l a b n o rm a lities (Heller, 1987; Dlu -gosz & Bracken , 1992). Neverth eless, th e im p li-cation s of th ese fin d in gs for h u m an b ein gs are u n clea r b eca u se o f d ifferen ces in th e m o d e o f exp o su re to ca ffein e, th e a m o u n ts co n su m ed , an d m etab olism of th e d ru g. However, d esp ite a p ro lifera tio n o f stu d ies o n p regn a n t wo m en in re c e n t ye a r s, t h e c o n c lu sio n s a re c o n t r o -ve r sia l. A m e t a - a n a lyt ic a p p r o a c h wa s u se d h ere to d eterm in e th e qu an titative su m m ary of th ese stu d ies.
M aterial and methods
Study selection
A Med lin e sea rch from 1966 to 1995 p ro d u ced twen ty-six ep id em iological p u b lication s on th e relation sh ip b etween caffein e an d b irth weigh t an d d u ration of h u m an p regn an cy. Th ese stu d -ie s h a d in ve stiga te d th e e ffe ct o f ca ffe in e o n low b irth weigh t (LBW – b irth weigh t less th an 2,500 gra m s), in tra u terin e growth reta rd a tio n (IUGR – b irth weigh t u n d er th e 10th p ercen tile
for gestation al age), an d p reterm d elivery (ges-ta tio n a l a ge o f le ss th a n 37 we e ks). A sco r in g syst e m d e ve lo p e d b y t h e U K Nu t r it io n a l Ep i-d e m io lo gy Gro u p fo r t h e Nu t r it io n So cie t y (U KNEGNS, 1993) wa s a d a p te d to ra n k th e overa ll q u a lity o f p a p ers in a n o b jective m a n -n e r. Ba se d o -n th e syste m , se p a ra te sco ri-n g m eth od s were u sed for case-con trol an d coh ort stu d ie s. Fo r ca se -co n tro l stu d ie s, th re e a re a s were scored : qu ality of caffein e assessm en t, recru it m e n t o f su b je ct s, a n d a n a lysis o f t h e re -su lts. Coh ort stu d ies were scored in fou r areas: ca ffein e a ssessm en t, d efin itio n o f th e co h o r t, a scerta in m en t of ou tcom e, a n d a n a lysis of re-su lts. Th is scorin g system allowed for a classifi-cation of th e stu d ies in a ran ge from zero to 10.
Data extraction
Wh en th e effect estim ate an d its stan d ard error fo r h e a vie st ca ffe in e co n su m p tio n a s co m -p a re d to n o n e o r lowe st co n su m -p tio n we re p rovid e d , th e y we re sim p ly co p ie d d ire ctly fro m th e rep o rt. Wh en co n fid en ce lim its were p rovid e d ra t h e r t h a n t h e st a n d a rd e rro r, t h e latter was calcu lated . Con sid erin g th at th e 95% con fid en ce in terva l for a n estim a te is eq u a l to (estim ate ± 1.96 stan d ard error) th an for a risk estim ate with a given 95% con fid en ce in terval, th e estim ated stan d ard error was calcu lated as follows: stan d ard error = (log u p p er lim it of th e con fid en ce in t erv a l - log est im a t e of risk )/1.96. Wh e n o n ly a p va lu e wa s give n , in ste a d o f a sta n d a rd e rro r o r co n fid e n ce in te r va l, a te st-b ased stan d ard error was estim ated as follows: st a n d a rd error = log est im a t e/t or z v a lu e o r st a n d a rd error = coefficien t est im a t e/t or z v a lu e; wh e re t o r z is th e va lu e o f th e sta tistic co rresp o n d in g to th e p va lu e (e.g., Zp= 1.96 if
p = 0.05, two -ta ile d te st). Assu m in g th a t th e stu d y o u tco m e s we re ra re in a ll p o p u la tio n s an d su b grou p s u n d er review, relative risks an d od d s ratios were p ooled togeth er.
Statistical meta-analysis
estim ated stan d ard error as 1/ SE2(Green lan d , 1987). Th e p o o le d su m m a r y o f t h e st u d y re -su lt s wa s ca lcu la te d a s th e e xp o n e n tia l o f th e we igh te d su m o f th e re su lts (S log est im a t e* 1/v a ria n ce) d ivid ed b y th e su m o f th e weigh ts
(S 1/v a ria n ce). Th e sta n d a rd erro r o f th is esti-m a te wa s ca lcu la te d a s th e in ve rse o f th e sq u are root of th e su m of th e weigh ts. Th e 95% con fid en ce in terval for th e estim ate was calcu-lated by (p ool estim ate ± 1.96 stan d ard error). A te st o f sign ifica n ce o f wh e th e r th e a ssu m e d com m on valu e was zero was given by Z = (p ool estim ate/stan d ard error), wh ich h as a stan d ard n orm al d istrib u tion .
However, th e a d eq u a cy o f th e p o o led esti-m ate as a esti-m eta-an alytic su esti-m esti-m ary of th e effect u n d er stu d y d ep en d s o n th e h o m o gen eity a s-su m p tio n , i.e., th a t th e stu d ies a re estim a tin g th e sa m e va lu e fo r th e e ffe ct a n d th a t, a p a r t fro m b ia s, th e d iffe re n ce s o b se r ve d a m o n g th e m a re d u e to ra n d o m e rro r. Th e sta tistica l test o f h o m o gen eity u sed wa s ch i- sq u a red = S stu d y w eigh t (stu d y estim ate-p ooled estim ate), wh ich h a s a ch i-sq u a red d istrib u tio n with d e-gre e s o f fre e d o m o n e le ss th a n th e n u m b e r o f stu d ies.
Results
Caffeine and birth weight
Twe n ty-two stu d ie s (Ma u & Ne tte r, 1974; va n d e n Be rg, 1977; Ar n a n d ova & Ka tsu lov, 1978; So ika , 1979; Ku zm a & So ko l, 1982; Lin n e t a l., 1982; Fu ru h ash i et al., 1985; Watkin son & Fried , 1985; Be a u la c-Ba illa ge o n & De sro sie rs, 1987; Ma rtin & Bra cke n , 1987; Mu ñ oz e t a l., 1988; Bro o ke e t a l., 1989; Ca a n & Go ld h a b e r, 1989; Fen ster et al., 1991; Olsen et al., 1991; Peacock et al., 1991; McDon ald et al., 1992; God el et al., 1992; Mills et al., 1993; Fortier et al., 1993; Lar-ro q u e et a l., 1993; Sh u et a l., 1995) fo cu sed o n b irth we igh t. Mo st o f th e m sh owe d , in th e cru d e a n a lysis, th a t co ffe e o r ca ffe in e wa s re -la te d to lowe r b irth we igh ts (Ma u & Ne tte r, 1974; va n d e n Be rg, 1977; Arn a n d ova & Ka t su lov, 1978; So ika , 1979; Lin n e t a l., 1982; Fu -ru h a sh i e t a l., 1985; Wa tkin so n & Frie d , 1985; Ma rtin & Bra cke n , 1987; Ca a n & Go ld h a b e r, 1989; God el et al., 1992; Fortier et al., 1993; Mills e t a l., 1993), th e m a jo rity o f th e se d iffe re n ce s b e in g sta tistica lly sign ifica n t. Do se -re sp o n se e ffe cts we re d e m o n stra te d in e igh t stu d ie s (Mau & Netter, 1974; van d en Berg, 1977; Mar-tin & Bracken , 1987; Brooke et al., 1989; Fen ster et a l., 1991; Pea co ck et a l., 1991; McDo n a ld et a l., 1992; Fo rtier et a l., 1993). It wa s a lso clea r
from th ese stu d ies th at d rin kin g coffee was rela te d to sm o kin g (va n d e n Be rg, 1977; Arn a n d ova & Katsu lov, 1978; Lin n et al., 1982; Watkin son & Fried , 1985; Martin & Bracken , 1987; Fen -ster et al., 1991; Olsen et al., 1991; God el et al., 1992; La rro q u e e t a l., 1993; Mills e t a l., 1993) a n d , in so m e o f th e m , to a lco h o lic b e ve ra ge co n su m p tio n (Ar n a n d ova & Ka tsu lov, 1978; Ma rtin & Bra cke n , 1987; Fe n ste r e t a l., 1991; Olsen et al., 1991; Mills et al., 1993). After allow-in g fo r sm o kallow-in g, twe lve o f se ve n te e n stu d ie s sh owe d th a t ca ffe in e wa s still re la te d to LBW (Ma u & Ne tte r, 1974; Ku zm a & So ko l, 1982; Watkin son & Fried , 1985; Beau lac-Baillageon & De sro sie rs, 1987; Ma rtin & Bra cke n , 1987; Mu ñ oz e t a l., 1988; Ca a n & Go ld h a b e r, 1989; Fen ster et al., 1991; Olsen et al., 1991; Peacock et al., 1991; McDon ald et al., 1992; Fortier et al., 1993). An o th e r stu d y wa s re stricte d to n o n -sm okers an d th e association rem ain ed p resen t (Peacock et al., 1991).
Am o n g th e se stu d ie s, o n ly th irte e n we re u sed for th e p ooled estim ation (Mau & Netter, 1974; van d en Berg, 1977; Ku zm a & Sokol, 1982; Lin n et al., 1982; Martin & Bracken , 1987; Caan & Go ld h a b e r, 1989; Fe n ste r e t a l., 1991; Olse n et a l., 1991; McDo n a ld et a l., 1992; Mills et a l., 1993; Fortier et al., 1993; Larroq u e et al., 1993; Sh u e t a l., 1995). Th e re m a in in g n in e re p o rts n eith er p rovid ed th e estim ate an d its stan d ard error n or p erm itted extra ctio n o f sta n d a rd errors by p u b lish in g relative risks, con fid en ce in -terva ls, o r p va lu es. Th ree stu d ies were o n th e effect of caffein e on m ean b irth weigh t (Ku zm a & Sokol, 1982; La rroq u e et a l., 1993; Sh u et a l., 1995), seven on LBW (Ma u & Netter, 1974; va n d e n Be rg, 1977; Lin n e t a l., 1982; Ma rtin & Bracken , 1987; Caan & Gold h ab er, 1989; Olsen e t a l., 1991; Fo rtie r e t a l., 1993), o n e o n IU GR (Mills et a l., 1993), a n d two in vestiga ted b o th , LBW an d IUGR (Fen ster et al., 1991; McDon ald e t a l., 1992). Mo re d e ta ile d in fo r m a tio n a n d q u a lity sco r in g o f th e se stu d ie s a re sh own in Tab le 1.
Tab le 2 p resen ts th e resu lts of rean alyses of th e stu d ie s. Th e stu d ie s b y Ku zm a & So ko l (1982), La rro q u e e t a l. (1993) a n d Sh u e t a l. (1995) p resen ted resu lts in term s of m ean b irth weigh t accord in g to caffein e con su m p tion . Th e weigh ted m ean of th ese resu lts was -42.99 (95% CI: -32.04 to -53.94; p <0.001), in d ica tin g th a t, a m o n g h e a vy co n su m e rs, n e wb o rn s we re a b ou t 43g ligh ter a s com p a red to n ewb orn s of m o th ers wh o co n su m ed lower a m o u n ts o r n o caffein e. Th e h om ogen eity test was n ot sign ifi-can t (p >0.05).
-p ared to n on e or lower am ou n ts was 1.33 (95% CI: 1.22-1.44; p <0.001) (Figu re 1). Th is p o o led estim a te su ggests th a t th ere is a 33% in crea se in risk of LBW am on g m oth ers wh o con su m ed th e la rge st a m o u n ts o f ca ffe in e th ro u gh o u t p re gn a n cy. Th e h o m o ge n e ity te st, h owe ve r, sh owed a sign ifican t resu lt, in d icatin g th at th e stu d ies were h igh ly h eterogen eou s an d sh ou ld th u s n o t b e su m m a rize d in a sin gle e stim a te
(p <0.001). Later calcu lation s exclu d in g th e two o u tlier stu d ies (Ma rtin & Bra cken , 1987; Ca a n & Gold h ab er, 1989) p rod u ced a su m m ary relative risk o f 1.29 (95% CI: 1.181.41) a n d a h o -m ogen eity test with a p valu e greater th an 0.10. Wh e n IU GR wa s th e o u tco m e o f in te re st, th e p ooled effect of th e th ree stu d ies wh ich sat-isfied in clu sion criteria was 1.24 (95% CI: 1.05-1.43; p <0.01), su ggestin g th at h eavy con su m ers
Tab le 1
Summary o f the e p id e mio lo g ic stud ie s o n the e ffe c t o f c affe ine o n b irth we ig ht and d uratio n o f p re g nanc y use d in the me ta-analysis
Study Design Sample size Caffeine source M ain result Q uality scoring
Mau & Ne tte r, 1974 c o ho rt 5,220 c o ffe e asso c iatio n with LBW 6
b ut no t p re maturity
We athe rsb e e e t al., 1977 c o ho rt 489 c o ffe e , te a, c o la d rinks asso c iatio n with p re maturity 6
van d e n Be rg , 1977 c o ho rt 15,000 c o ffe e asso c iatio n with LBW and 7
p re te rm d e live ry
Kuzma & So ko l, 1982 c o ho rt 5,093 no t p re se nte d asso c iatio n with d e c re ase d 7
me an b irth we ig ht
Be rko witz e t al., 1982 c ase -c o ntro l 175/ 313 c o ffe e , te a no asso c iatio n with p re maturity 8
Linn e t al., 1982 c o ho rt 12,205 c o ffe e , te a no asso c iatio n with LBW 7
o r p re te rm d e live ry
Martin & Brac ke n, 1987 c o ho rt 3,891 c o ffe e , te a, asso c iatio n with LBW b ut 7
c o la d rinks, me d ic ine s no t p re maturity
Caan & G o ld hab e r, 1989 c ase -c o ntro l 131/ 136 c o ffe e , te a, c o la d rinks asso c iatio n with LBW 8
O lse n e t al., 1991 c o ho rt 11,858 c o ffe e , te a asso c iatio n with LBW b ut 7
no t with p re te rm d e live ry
Fe nste r e t al., 1991 c ase -c o ntro l 87/ 1,143 c o ffe e , te a, c o la d rinks asso c iatio n with IUG R and 6
LBW b ut no t p re te rm d e live ry
W illiams e t al., 1992 c ase -c o ntro l 795/ 2,252 c o ffe e , te a asso c iatio n with p re te rm d e live ry 8
Mc Do nald e t al., 1992 c o ho rt 40,445 c o ffe e asso c iatio n with p re te rm d e live ry 7
Mills e t al., 1993 c o ho rt 431 c o ffe e , te a, c o la d rinks, no asso c iatio n with IUG R 6
c o c o a, me d ic ine s
Fo rtie r e t al., 1993 c o ho rt 7,025 c o ffe e , te a, c ho c o late , asso c iatio n with IUG R b ut 6
c o la d rinks no t LBW o r p re te rm d e live ry
Larro q ue e t al., 1993 c o ho rt 628 c o ffe e , te a, c o c o a, asso c iatio n with d e c re ase d 6
c o la d rinks me an b irth we ig ht
Pasto re & Savitz, 1995 c ase -c o ntro l 408/ 490 c o ffe e , te a, c o la d rinks, no asso c iatio n with p re te rm d e live ry 7
o the r c affe inate d so ft d rinks
Shu e t al., 1995 c o ho rt 712 c o ffe e , te a, c o la d rinks no asso c iatio n with me an b irth we ig ht 6
LBW: lo w b irth we ig ht
h a ve a 24% in cre a se in risk o f d e live rin g a sm a ll-fo r-gesta tio n a l-a ge ch ild . Howe ver, th e h om ogen eity test was also sign ifican t, in d icat -in g th a t d eriv-in g a p o o led estim a te wo u ld n o t b e ad eq u ate (p <0.001).
Caffeine and preterm delivery
Eleven stu d ies focu sed on gestation al age ( van d e n Be rg, 1977; We a th e rsb e e e t a l., 1977; Berkowitz et al., 1982; Lin n et al., 1982; Watkin -so n & Frie d , 1985; Ma rtin & Bra cke n , 1987; Olsen et al., 1991; William s et al., 1992; McDon -a ld e t -a l., 1992; Fo r t ie r e t -a l., 1993; P-a st o re &-amp; Sa vitz, 1995) a n d o n ly th ree fo u n d sign ifica n t association (Weath ersb ee et al., 1977; van d en Be rg, 1977; Willia m s e t a l., 1992) ( Ta b le 1). Th e e igh t re m a in in g st u d ie s, in clu d in g t wo sp ecifically d esign ed to m easu re th is ou tcom e
(Berkowitz et a l., 1982; Pa sto re & Sa vitz, 1995) d id n o t d e te ct a n y a sso cia tio n . Un d e r th e a s-su m p tio n o f h o m o gen eity a m o n g th e stu d ies, th e we igh te d a n a lysis o f th e e ffe ct o f ca ffe in e o n ge sta tio n a l a ge sh owe d a 24% in cre a se in risk (co m b in e d e stim a te : 1.24; 95% CI: 1.11-1.38; p <0.001) a m o n g h e a vy co n su m e rs (Fig-u re 2). Th is re s(Fig-u lt wa s o b t a in e d fro m e st i-m ates rep orted by eigh t stu d ies ( Weath ersb ee e t a l., 1977; Be rkowitz e t a l., 1982; Lin n e t a l., 1982; Olse n e t a l., 1991; Willia m s e t a l., 1992; Mc D o n a ld e t a l., 1992; Fo r t ie r e t a l., 1993; Pa st o re & Sa vit z, 1995). Howe ve r, t h e h o m o -gen eity test resu lt wa s sta tistica lly sign ifica n t (p <0.001), in d ica t in g t h a t a p o o le d e st im a t e sh o u ld n o t b e va lid . Th e exclu sio n o f th e o u t-lie r st u d y o f We a t h e rsb e e e t a l (1977) d id n o t e n h a n ce h o m o ge n e it y a m o n g t h e re m a in in g stu d ies (p < 0.001).
Tab le 2
Summary o f re analyse s o f stud ie s o f c affe ine and b irth we ig ht and d uratio n o f p re g nanc y
Study Log estimate Standard error Weight
M ean birth weight
Kuzma & So ko l, 1982 3.76120 1.190253 0.031746
Larro q ue e t al., 1993 3.68879 65 0.000236
Shu e t al., 1995 3.89182 117.346938 0.000072
Low Birth Weight
Mau & Ne tte r, 1974 0.457424 0.154015 42.15735
van d e n Be rg , 1977 0.216722 0.082403 147.2670
Linn e t al., 1982 0.182321 0.146777 46.41801
Martin & Brac ke n, 1987 1.526056 0.421081 5.639862
Caan & G o ld hab e r, 1989 1.078409 0.606402 2.719433
O lse n e t al., 1991 0.182321 0.206870 23.36711
Fe nste r e t al., 1991 0.693147 0.457188 4.784216
Mc Do nald e t al., 1992 0.357674 0.176236 32.19655
Fo rtie r e t al., 1993 -0.01005 0.324484 9.497586
Intrauterine Growth Retardation
Fe nste r e t al., 1991 1.064710 0.442250 5.112856
Mc Do nald e t al., 1992 0.329303 0.180507 30.69116
Mills e t al., 1993 0.104360 0.118425 71.30436
Preterm delivery
We athe rsb e e e t al., 1977 2.120263 0.855556 1.366165
Be rko witz e t al., 1982 -0.69314 0.402274 6.179533
Linn e t al., 1982 0.173953 0.166746 35.96579
O lse n e t al., 1991 0.182321 0.177707 31.66565
W illiams e t al., 1992 0.788457 0.206870 23.36711
Mc Do nald e t al., 1992 0.215111 0.187298 28.50580
Fo rtie r e t al., 1993 -0.17435 0.309253 10.45616
Discussion
Me ta -a n a lysis wa s u se d fo r co n tra stin g a n d co m b in in g re su lts o f d iffe re n t stu d ie s o n th e e ffe ct o f ca ffe in e o n h u m a n p re gn a n cy o u t com es, p articu larly b irth weigh t an d gestation a l a ge a t b ir th . Ap a rt fro m p rovid in g a co m -b in ed effect, m eta-an alysis is u sefu l for in vesga tin g wh eth er th e p o o led stu d ies a re q u a n ti-tatively con sisten t. Taken togeth er, in a p u rely d escrip tive an alysis, th ese stu d ies su ggested a p ro b a b le e ffe ct o f ca ffe in e o n b irt h we igh t ,
wh ile gestation al age d id n ot seem to b e affect-ed . However, weigh taffect-ed an alyses sh owaffect-ed th at it was n ot p ossib le to d erive a su m m ary estim ate b a se d o n th e m a jo r ity o f a va ila b le p u b lish e d stu d ies, sin ce h eterogen eity am on g th e stu d ies was h igh ly sign ifican t. Th e sign ifican t resu lts of th e h o m o ge n e ity te sts a re d ire ct e vid e n ce o f th e in con sisten cy of th e stu d ies on th e effect of caffein e in h u m an p regn an cy.
Association b etween an exp osu re an d a d is-ease ob served in a sin gle stu d y m ay d ep en d on th e p o p u la tio n sa m p le d , le ve l o f e xp o su re in
Fig ure 1
Re lative risk o f LBW (e stimate and 95% c o nfid e nc e inte rval) in hig h c affe ine c o nsume rs c o mp are d to no n
o r lo w c o nsume rs.
0,1
re
la
ti
v
e
r
is
c
(
lo
g
s
c
a
le
)
1 10 100
All Stud ie s Fo rtie r e t al.,
1993 O lse n e t al., 1991 Linn e t al., 1982 van d e n Be rg , 1977 McDo nald
e t al., 1992 Mau &
Ne tte r, 1974 Fe nste r
e t al., 1991 Caan &
Go ld hab e r, 1989 Martin & Bracke n, 1987
Fig ure 2
Re lative risk o f p re te rm d e live ry (e stimate and 95% c o nfid e nc e inte rval) in hig h c affe ine c o nsume rs c o mp are d to no n
o r lo w c o nsume rs.
0,1
re
la
ti
v
e
r
is
c
(
lo
g
s
c
a
le
)
1 10 100
All Stud ie s Be rko witz
e t al., 1982 Pasto re
& Savitz, 1995 Fo rtie r e t al.,
1993 Linn e t al., 1982 O lse n e t al., 1991 McDo nald e t al., 1992 Williams
e t al., 1992 We athe rsb e e
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