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OBSTETRICS

Maternal caffeine consumption during pregnancy and the risk of miscarriage: a prospective

cohort study

iaoping !eng" #h$% Ro&ana Odouli" MS#'% $e()un *i" M$" #h$

OBJECTIVE: The o+,ective of the study -as to e&amine -hether the risk of miscarriage is

associated -ith caffeine consumption during pregnancy after controlling for pregnancy(

related symptoms.

STUDY DESIGN: This -as a population(+ased prospective cohort study.

RESULTS: /n increasing dose of daily caffeine intake during pregnancy -as associated -ith

an increased risk of miscarriage" compared -ith no caffeine intake" -ith an ad,usted ha0ard

ratio 1a'R2 of 3.45 1678 con9dence interval .6; to 5.372 for caffeine intake of less than 5

mg<day" and a'R of 5.5; 13.;4 to ;.=62 for intake of 5 or more mg<day" respectively.

>ausea or vomiting during pregnancy did not materially affect this o+served association" nor

did the change in intake pattern of caffeine during pregnancy. In addition" the magnitude of

the association appeared to +e stronger among -omen -ithout a history of miscarriage 1a'R

5.;;" 3.4? to ;.=@2 than that among -omen -ith such a history 1a'R .?3" .;4 to 3.642.

CONCLUSION: Our results demonstrated that high doses of caffeine intake during

pregnancy increase the risk of miscarriage" independent of pregnancy(related symptoms.

Key words: a+ortion" caffeine" miscarriage" spontaneous

Cite this article as: !eng " Odouli R" and *i $(). Maternal caffeine consumption during

pregnancy and the risk of miscarriage: a prospective cohort study. /m A O+stet ynecol

5?%36?:[email protected]([email protected]?.

affeine" 3";"@(trimethyl&anthine" is among the most freuently ingested

pharmacologically active su+stances in the -orld. Caffeine can readily cross

the placental +arrier to the fetus% its clearance is prolonged in pregnant -omen"

and its meta+olism rate is lo- in the fetus +ecause of lo- levels of en0ymes. It

may also inDuence cell development through increasing cellular cyclic adenosine

monophosphate concentrations and decrease intervillous placental +lood Do- via increasing

circulating catecholamines. Therefore" caffeine could have an adverse effect on fetal

C



development. Indeed" caffeine intake has +een reported to increase the risk of miscarriage.

/lthough numerous studies on maternal caffeine consumption and the risk of miscarriage

have +een pu+lished since the 36?s" the effect of caffeine intake on the risk of miscarriage

remains controversial +ecause of methodological limitations in past studies. Many studies

have relied on retrospective information" -hich is su+,ect to recall +ias. Some had only a

small num+er of participants" -hich limited their po-er to detect an effect. Some did not take

into account potential confounding factors such as smoking" alcohol consumption" and most

importantly" pregnancy(related symptoms including nausea and vomiting. inally" some

recruited -omen -ho sought prenatal care at their 3;th to 5?th -eeks of gestation" therefore

too late in pregnancy to study miscarriage. Such controversy has led to the uncertainty a+out

the health effects of caffeine consumption during pregnancy among +oth clinicians and

pregnant -omen alike. In the Fnited States" coffee" tea" and car+onated soft drinks are the

main sources of caffeine intake. Mean daily caffeine consumption from these sources -as

estimated around 3=(3@ mg per day for adults and 7? mg per day for pregnant -omen"

respectively. The o+,ective of this population(+ased prospective study -as to e&amine the

effect of maternal caffeine intake during pregnancy on the risk of miscarriage" taking into

account a num+er of potential confounders" especially the impact of nausea or vomiting

during pregnancy.

MATERIALS AND M ETHODS

The study -as conducted among pregnant mem+ers of the )aiser #ermanente Medical Care

#rogram 1)#MC#2" a group model(integrated health care delivery system. $uring a 5 year

period from Octo+er 366= through Octo+er 366?" all )#MC# -omen -ho resided in the San

rancisco and South San rancisco areas and had a positive pregnancy test in these facilities

-ere identi9ed as potentially eligi+le su+,ects. The )#MC# facilities reuire all -omen -ho

suspect that they might +e pregnant to undergo a pregnancy test at the )#MC# la+oratory

regardless of -hether they have already performed home pregnancy tests. /ny -oman -ho

su+mitted a urine or +lood sample for a pregnancy test -as given a Dyer e&plaining the

purpose of the study and -as informed of the possi+ility of +eing contacted for this study. /

postage(paid and self(addressed return refusal postcard -as included -ith the Dyer so that

-omen -ho did not -ish to +e contacted for the study could inform us. Specially trained

female intervie-ers contacted all -omen -ho did not return their refusal cards. /ny -oman



-ho spoke English and intended to carry her pregnancy to term at the time of contact -as

considered eligi+le for the study. !omen already included in the study for 3 pregnancy -ere

not eligi+le to +e included for su+seuent pregnancies during the study period.

Of 5@56 eligi+le -omen" 3=4 1=82 -ere contacted too far along in their pregnancy

1more than 37 -eeks2 for intervie-% ;3@ 13582 initially agreed to participate +ut -ere una+le

to schedule an intervie-% 33?7 14;82 refused to participate% and ultimately 3=; 1;682

completed the intervie-. The main reasons for refusal -ere too +usy" not interested" and too

stressful to participate. / more detailed description of the study design and methods can +e

found else-here.

Exposre !ssess"e#$

Information on e&posure to caffeine consumption during pregnancy -as o+tained during an

in(person intervie- conducted soon after a -omanGs pregnancy -as con9rmed 1the median

gestational age at intervie- -as @3 days2. !omen -ere asked to report their intake of

+everage including caffeine(containing +everages since their last menstrual period 1*M#2.

They -ere asked a+out the types of their drinks% timing of initial drink% the freuency and

amount of the intake% -hether they changed consumption patterns since +ecoming pregnant%

and" if so" the time" the freuency" and the amount of consumption after the change. !omen

might report their caffeine intake on either a daily or -eekly +asis and then average daily

intake -as calculated. Sources of caffeine included coffee 1caffeinated or decaffeinated2" tea

1caffeinated or decaffeinated2" caffeinated soda 1including 3@ +rands" such as Coca(Cola" Big

Red" and #epsi(Cola" etc2" and hot chocolate. !e used the follo-ing conversion factors to

estimate the amount of caffeine intake: for every 37 m* of a +everage" -e estimated 3 mg

for caffeinated coffee" 5 mg for decaffeinated coffee" ;6 mg for caffeinated tea" 37 mg for

caffeinated soda" and 5 mg for hot chocolate. Information on potential confounders" such as

maternal age" race" education" household income" marital status" smoking" alcohol

consumption" Aacu00i use" e&posure to magnetic 9elds 1M2 during pregnancy" and symptoms

related to pregnancy such as nausea and vomiting -ere also collected during the in(person

intervie-.

%re&#!#'y o$'o"e



#regnancy outcomes up to 5 -eeks of gestation -ere determined for all participants through

the follo-ing ; methods: 132 searching the )#MC# inpatient or outpatient data+ases" 152

revie-ing medical records" and 1;2 contacting participants -hose outcomes could not +e

determined +y using the previous 5 methods. Because" +y de9nition" no miscarriage occurs

after 5 -eeks of gestation" pregnancy status -as censored at 5 -eeks of gestation for those

pregnancies that continued +eyond 5 -eeks. !e had information on pregnancy outcomes for

all participants at 5 -eeks of gestation. More than 678 of miscarriages in our study

population occurred +efore 37 -eeks of gestation. Because -e recruited -omen at an early

gestational age" a total of 35 su+,ects 17682 had already had a miscarriage at the time of

initial contact for their participation. These su+,ects -ere intervie-ed soon after their

miscarriage 1median delay 36 days2" and information on caffeine intake -as ascertained only

up to the end of pregnancy.

S$!$(s$('!) !#!)ys(s

The Co& proportional ha0ards regression -as used to take into account possi+le differing

gestational ages at study entry +et-een the e&posed 1caffeine intake2 and une&posed. By

using the Co& model -ith left truncation" -e e&amined the association +et-een caffeineconsumption and the risk of miscarriage at any speci9c gestational age only for those -omen

-ho had entered into the study and remained pregnant at the +eginning of that speci9c

gestational age. The interval +et-een conception and study entry -as truncated in this case

1ie" treated as missing follo-(up time2. Fsing the Co& model also ena+led us to easily assess

-hether the effect of caffeine consumption on the risk of miscarriage changed -ith

gestational age.

Entry time -as de9ned as gestational age at the positive pregnancy test +ecause -e

started to follo- up a -omanGs pregnancy at her positive pregnancy test. The median

gestational age at entry for the entire cohort -as 4 days. The follo-(up time -as gestational

age in days. estational age -as determined +y ultrasound 13=.482" an o+stetrician 17.682"

or the self(reported last menstrual period 1;5.@82 if the determination +y ultrasound or

o+stetricians -as not availa+le. /ll participants -ere follo-ed up until miscarriage"

termination of pregnancy +ecause of other causes 1eg"ectopicpregnancy2" or 5 -eeks of

gestation.



The average daily caffeine intake during pregnancy -as categori0ed as " less than

5 mg<day" or 5 or more mg<day in the overall analysis. #otential confounders" such as

maternalage" race" education" household income" marital status" smoking" alcohol

consumption" Aacu00i use" M e&posure" and nausea and vomiting -ere included into the

CO model for ad,ustment. / test for trend -as performed -ith the categories of caffeine

intake as an ordinal scale. /ll statistical analyses -ere performed using S/S 6. 1S/S

Institute" Cary" >C2.

RESULTS

Overall 3@5 of -omen 13=.3?82 miscarried. !hereas 5=4 -omen 15782 reported no

consumption of any caffeine



containing +everages during pregnancy" =;7-omen1=82 reported (5 mg of caffeine

intake per day" and 3=4 -omen 13782 had 5 mg or more of daily caffeine consumption.

Ta+le 3 compares the various characteristics of -omen -ho -ere at different levels of

caffeine consumption. Caffeine intake -as associated -ith a variety of risk factors for

miscarriage" such as age of ;7 years or older% having had aprior miscarriage% an a+sence of

vomiting% and smoking" alcohol consumption" and use of Aacu00i during pregnancy. /lso"

-omen -ith higher caffeine consumption -ere more likely to +e -hite and to have a higher

household income.

/n increasing amount of caffeine intake -as associated -ith an increased risk of

miscarriage 1Ta+le 52. Compared -ith nonusers" -omen -ho consumed (

5mgcaffeinedailyhadanincreased risk of miscarriage 1378 vs 3582" and

thecorrespondingrisk-asmuchgreater 15782 among -omen -ho consumed more than 5



mg caffeine daily. /fter ad,ustment for potential confounders including maternal age" race"

education" house hold income" marital status" previous miscarriage" smoking" alcohol

consumption" Aacu00iuse" Me&posure" and nausea and vomiting" the ha0ard ratio of

miscarriage -as 3.45 1678 con9dence interval HCI" .6;to5.372 and 5.5; 1678 CI" 3.;4 to

;.=62 for daily caffeine consumption of (5 mg and 5 mg or more" respectively 1# for

trend.32. Regarding the sources of caffeine" =;8 of total caffeine consumed -as from

coffee. There -ere 375 -omen 13682 -hose source of caffeine -as solely from coffee" 56;

1;=.@82 from sources other than coffee" and the remaining ;73 -omen 14;.682 from coffee

and non coffee sources 1coffee" tea" softdrinks" etc2. !e performe dastrati9ed analysis

according to the source of caffeine" and the association remained" regardless of the sources.

Ta+le ; sho-s the relationship +et-een caffeine consumption and the risk of

miscarriage separately for -omen -hose pattern of caffeine consumption changed during

pregnancy. / total of =;3 -omen 1@682 reduced their caffeine consumption since they

+ecame pregnant and 375 13682 maintained the same consumption pattern" -hereas 3= 1582

increased their consumption during the pregnancy. Caffeinein take of 5 mg or greater

remained associated -ith an increased risk of miscarriage" regardless of -hether a -oman

changed her pattern of caffeine intake after pregnancy" although the estimate in each stratum

-as no longer statistically significant +ecause of reduced sample si0e from strati9cation. The



num+er of -omen -ho increased their caffeine intake after pregnancy -as too small to have

a meaningful interpretation.

To e&amine -hether the o+served association -as inDuenced +y other risk factors" -e

conducted additional analyses of the association strati9ed +y presence or a+sence of nausea"

smoking during pregnancy" and a history of miscarriage. To increase the sta+ility of the

estimates in these analyses" -e categori0ed the caffeine consumption into less than 5

mg<day or 5 mg<day or more +ecause the risk of miscarriage among -omen -ithout any

consumption of caffeine and those -ith consumption of caffeine less than 5mg<day -as

uite similar. The association e&isted among -omen +oth -ith and -ithout the symptom of

nausea during pregnancy" although the association -as slightly stronger among -omen -ith

the symptom 1Ta+le 42. / similar pattern of the association -as o+served for the symptom of

vomiting during pregnancy.



The effec to caffeine consumptionon miscarriage -as higher in the nonsmoker group

1ad,usted ha0ard ratio Ha'R 5.4" 678 CI" 3.;7 to ;.62 than the smoker group 1a'R 3.46"

678 CI" .;= to =.?2 and -as only statistically signi9cant in the nonsmoker group. In

addition" caffeineGs effect on the risk of miscarriage remained strong among -omen -ithout a

history of miscarriage 1a'R 5.;;" 678 CI" 3.4? to ;.=@2" -here as the association no longer

e&isted among -omen -ith such a history 1a'R .?3" 678 CI" .;4 to 3.642 1Ta+le 42. The

test for the interaction -as +orderline signi9cant 1# .72. To determine -hether the effect of

caffeine on the risk of miscarriage varied +y gestational age at miscarriage" -e e&amined the

effect separately for miscarriages that occurred +efore and after ? -eeks of gestation. / total

of 7@ miscarriages 1;;82 occurred +efore ? gestational -eeks" and 337 1=@82 occurred on or

after that. 'igher caffeine consumption -as associated -ith higher risk for +oth early and late

miscarriage. 'o-ever" the association appeared to +emore pronounced for later rather than

earlier miscarriage 1Ta+le 72.



COMMENT

In this prospective cohort study" -e demonstrated an elevated risk of miscarriage associated

-ith caffeine consumption during pregnancy and a dose(response relationship -ith most of

the risk associated -ith caffeine consumptionat 5 mg or greater per day. This o+served

effect -as independent of many potential confounders including pregnancy related symptoms

such as nausea" vomiting" and aversion to caffeine consumption. Even among -omen -ho

never changed caffeine consumption pattern during pregnancy" there -as an almost ?8

increased risk of miscarriage associated -ith caffeine consumption of 5 mg< day or greater"

although it -as not statistically signi9cant +ecause of reduced sample si0e +y strati9cation.

inally" the increased risk of miscarriage appeared to+e due tocaffeine itself rather than other

possi+le chemicals in coffee +ecause caffeine intake from noncoffee sources sho-ed the

similarly increased risk of miscarriage 1Ta+le 52.

/lthough an increased risk of miscarriage associated -ith caffeine intake during

pregnancy has +een previously reported" a lack of adeuate control of potential confounders"

especially pregnancy(related symptoms such asnausea"vomiting"and aversion to caffeine"

limited the validity of those 9ndings. Some argued that the association -as an artifact

+ecause of confounding +y nausea and vomiting" -hich are generally associated -ith a lo-

risk of miscarriage and possi+le reduction of the consumption of caffeine +ecause of the

symptoms. !e ascertained detailed information on nausea and vomiting since the *M# and

for the immediate @ days +efore the intervie-. The association +et-een caffeine intake and

the risk of miscarriage remained after ad,ustment for nausea and vomiting" and the

association also continued to e&ist among -omen +oth -ith and -ithout nausea and vomiting

during pregnancy.

To address this issue more thoroughly" -e e&amined the association among -omen

-ith and -ithout actual change in caffeine consumption during pregnancy 1a direct control of

possi+le changes in caffeine consumption +ecause of underlying risk of miscarriage that had

+een the critical point of the criticism of the association2. !e e&amined the association

separately among those -ho reduced and -ho did not change their caffeine consumption

during pregnancy. 1The sample si0e -as too small to evaluate this issue for those -ho

increased their caffeine consumption during pregnancy.2The increased risk of miscarriage

associated -ith caffeine consumption still e&isted after the strati9cation. These results did not



support the argument that the o+served association -as due to confounding +y the pregnancy(

related symptoms that reduced +oth caffeine intake and the risk of miscarriage.

!e also o+served that the association appeared to +e stronger among -omen -ithout

other risk factors for miscarriage" for e&ample" -omen -ith no history of miscarriage" no

smoking during pregnancy" and the presence of nausea and<or vomiting 1Ta+le 42. /lthough

the underlying reason for this interaction is not kno-n at this time" it could +e that caffeine

intake is a lesser risk factor in the presence of other risk factors of miscarriage as is the likely

case among -omen -ith a history of repeated miscarriages. If our interpretation is correct"

this o+servation is consistent -ith our other 9nding that the association -as stronger among

later miscarriage 1Ta+le 72" -hich" unlike early miscarriage" are not largely due to kno-n

strong risk factors such as chromosomal a+normalities.

One limitation of the study is the potential misclassi9cation of caffeine intake.

Caffeine content in a cup of tea<coffee varies +y different +rands and +re-ing methods% it is

not practical to perform la+oratory analysis on caffeine content from consumed coffee and tea

in epidemiological studies. Even assays of +iological specimens have limitations +ecause

they can measure only caffeine intakes in the very recent past. Therefore" most studies

including ours used certain conversion factors to calculate caffeine amount given the sources

of caffeine and amount of intake provided +y the participants.

/nother concern is the potential recall +ias +ecause of some participants -ho -ere

intervie-ed soon after their miscarriage. To assess the potential e&istence of recall +ias" -e

conducted a strati9ed analysis +ased on -hether the intervie- -as conducted +efore or after

their miscarriage. The results -ere essentially the same" providing no evidence of recall +ias.

Therefore" -e com+ined the data in the 9nal analyses. Because of lo- participation rates"

selection +ias could +e a potential concern.



/lthough -e do not have information on caffeine intake for nonparticipants" -e

compared a fe- characteristics" including age and the rate of miscarriage +et-een

participants and nonparticipants. Both average age 1; vs 56 years2 and the rate of

miscarriage 13=.48 vs [email protected] for participants and nonparticipants -ere very similar"

providing some assurance against participation +ias. The strengths of the present study

included: 132 a cohort design" 152 a large study sample si0e" 1;2 recruitment of pregnant

-omen at early gestational ages for identi9cation of early miscarriages" 142 detailed

information on caffeine intake including all sources" changing patterns of intakes" and timing

and amount of intakes since *M#" and 172 ascertainment of detailed information on

pregnancy(related symptoms including nausea" vomiting" and aversion to caffeine

consumption during pregnancy. The availa+le information on nausea" vomiting" and e&istence

of aversion to caffeine consumption allo-ed us to e&amine -hether these factors e&plained

the o+served association of caffeine intake during pregnancy -ith the risk of miscarriage. In

conclusion" the results from our prospective cohort study supported previous 9ndings that

high caffeine consumption during pregnancy may increase the risk of miscarriage. !e

provided ne- evidence that the o+served association -as not likely the result of confounding

+y the pregnancy related symptoms of nausea" vomiting" and aversion to caffeine

consumption. Therefore" it may +e prudent to stop or reduce caffeine intake during pregnancy.



ACKNO*LEDGMENT

$e()un *i conceived the concept" designed thestudy"o+tainedfunding"oversa-thedata

collection and analyses" and -as involved in theinterpretationofresultsandpreparationof the

manuscript. iaoping !eng -as responsi+le for data analysis" interpretation of the data" and

preparation of the manuscript. Ro&ana Odouli -as involved in the data collection and

preparation of the manuscript. $e()un *i is the guarantor of this paper" -ho took full

responsi+ility for the conduct of the study" had access to the data" and controlled the decision

to pu+lish.

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