VaginalbleedinginveryearlypregnancyE.W.Harville1,4,A.J.Wilcox2,D.D.Baird2andC.R.Weinberg31DepartmentofEpidemiology,SchoolofPublicHealth,UniversityofNorthCarolina,ChapelHill,NC,275997435,2EpidemiologyBranchand3BiostatisticsBranch, NationalInstituteofEnvironmentalHealthSciences,Durham,NC27709,USA4Towhomcorrespondenceshouldbeaddressed.E-mail:ewh@unc.eduINTRODUCTION: Little is known about the occurrence and patterns of vaginal bleeding during the earliest stagesof pregnancy. We explore this in a prospective study of early pregnancy. METHODS: A total of 221 healthy womenkeptdailydiariesandprovideddailyurinesampleswhiletryingtobecomepregnant.Ofthese,151womenbecameclinicallypregnant [i.e. pregnancythat lasted>6weeksbeyondlast menstrual period(LMP)] duringthestudy.Diariesprovidedinformationondayswithvaginal bleedingandsexual intercourse. Urinehormoneassayswereusedtoidentifyovulationandimplantation. Womenwereinterviewedabout theirmedical historiesandlifestylefactors. RESULTS: A total of 14 women (9%) recorded at least 1 day of vaginal bleeding during the rst 8 weeks ofpregnancy. Twelve of these 14 pregnancies continued to a live birth. Bleeding tended to occur around the time whenwomenwouldexpecttheirperiods, althoughrarelyonthedayofimplantation. Bleedingwasnotassociatedwithintercourse. CONCLUSIONS: Early bleeding in clinical pregnancies is generally light, and not likely to be mistakenfor LMP. Thus, earlybleedingis unlikelytocontributetoerrors inLMP-basedgestational age. Wefoundnosupport forthehypothesis that implantationcanproducevaginal bleeding. Similarly, intercoursedidnot causebleeding. Nearly all women with bleeding went on to have successful pregnancies.Keywords:bleeding/rsttrimester/implantation/spontaneousabortionIntroductionBleeding is a common complication of pregnancy, with1015%of womenreportingsomebleedingduringtherstsixteen weeks of pregnancy (Ananthand Savitz, 1994). Ingeneral, bleeding is considered to be a risk factor for poor fetaloutcomes, includingspontaneousabortion, pretermdelivery,andlowbirthweight(Batzonetal., 1984). However, recallbiasmayexplainsomeofthesendings. Also, thetimingofbleedingisdifcult todetermineretrospectively, andstudieshavesometimesgroupedallbleedingduringonetrimesterorhalf a trimester of pregnancy (Ananth and Savitz, 1994;Everett,1997).Because of its timing, bleeding during early pregnancymight be mistaken for menses. Such bleeding has beenconjecturedto account for errorsin gestational age estimationusing the last menstrual period (LMP) method (Gjessing et al.,1999), especiallyamongpregnanciesthat endinmiscarriage(Iffyetal., 1972). Vaginalbleedinghasalsobeenthoughtinsome cases to accompany implantation (Speert andGuttmacher,1954).Wecarriedoutananalysisofdatafromaprospectivestudyof 151naturally-conceivedpregnancies inordertoexploretheseissuesinmoredetail.MaterialandmethodsWomenwhoplannedtobecomepregnant wererecruitedbymeans of newspaper and other advertisements in the localcommunity. The only selection criteria were that women had tobeatleast18yearsofage,andcouldhavenoknownfertilityproblems or serious health problems. We enrolled 221 eligiblewomenat thetimetheystoppedusinganymethodof birthcontrol (Table I). Nearlyall womenwere white,and 92%hadsome formal education beyond high school. One-third hadneverbeenpregnant(Wilcoxetal., 1988).Womencollecteddailyurinesamples(rst morningvoid)forupto6monthsiftheydidnotbecomepregnant,orforatleast 8 weeks after the last menstrual period if they did becomepregnant. At the time of urine collection, women also lled outdaily record cards with information on vaginal bleeding(numbersof padsandtamponsintheprevious24h). Somewomen recorded bleeding that was too light to require pads ortampons; we include these as`spotting'. Women also provideddaily records of sexual intercourse. As with the urine samples,these diary records were collected for at least 8 weeksfollowingthelastmenstrualperiod.Urinesamples wereassayedfor hCGusinganextremelysensitive immunoradiometric assay (Caneld et al., 1987). Thesensitivity of this assay was sufcient to provide an estimate ofthedayofimplantation. Implantationoftheblastocystisnotobservabledirectly, andthebest indirect marker ofimplant-ationishCG(Hearnetal.,1991).WeusedahighlysensitiveradioimmunoassayforhCGinrst-morningurinesamplestoidentifytheearliestdayofpregnancyonwhichhCGconcen-tration reached 0.15 ng/ml. Initial detection was typicallyHumanReproductionVol.18,No.9pp. 19441947,2003 DOI:10.1093/humrep/deg3791944 HumanReproduction18(9) EuropeanSocietyofHumanReproductionandEmbryology2003;allrightsreserved by guest on June 9, 2015http://humrep.oxfordjournals.org/Downloaded from followedbyasteadyexponentialriseofhCG(Wilcoxetal.,1999). Radioimmunoassays of daily urine samples wereperformedfor themajor metabolicproductsofestradiol andprogesterone. The ratio of these metabolites changes incharacteristic ways with the approach and occurrence ofovulation, providing a reliable means to identify dayofovulation(Bairdetal.,1995).Thevalidityofthismeasureof ovulation has been conrmed in subsequent studies (Dunsonetal.,2001;Ecochardetal.,2001).We dened `clinical pregnancy' as a pregnancy that lasted atleast6weeksbeyondtheLMP. Therewere151womenwhoconceivedaclinical pregnancyduringthestudy. Wedened`early bleeding' as >1 day of vaginal bleeding betweenconception and the end of follow-up. In nearly all cases,follow-up was through the week 8 after LMP. One woman whocollected data through her week 9 experienced spotting in week9; those data are included here. We included bleeding only if itwas distinct from the bleeding that accompanied the expulsionofanembryoorfetus. Nowomancontributedmorethanoneclinicalpregnancytothestudy.c2-tests were used for analyses of categorical variables.Whencellcountsweresmall,Pearsontestswereused. t-testswereusedforanalysesofcontinuousvariables.Informationonthewoman'smedical history, medications,smoking and other factors was collected by in-person interviewat the time that woman was enrolled. The protocol wasapprovedbytheNational Instituteof Environmental HealthSciences internal reviewboard, and informed consent wasobtained.ResultsAtotal of 9%of womenwithclinical pregnancies (14/151)reported at least 1 day of bleeding during early pregnancy. DatafromthesepregnancieswithbleedingareshowninFigure1.Bleeding was typically light, requiring only one or two pads ortamponsin24h. (Thispatternisincontrast tothebleedingreported with ordinary menstrual periods, for which women inour study typically used 48 pads on the heaviest days of ow.)Theheaviestbleedingduringearlypregnancywas5consecu-tive days, and a maximum of three pads or tampons were usedperday(LinFigure1).Thispregnancyendedinalivebirth.Weexploredthetimingofbleedinginrelationtoimplant-ation, and to the expected onset of menses. No woman reportedbleeding between the time of ovulation and implantation. Onlyonewoman(MinFigure1)hadanybleedingonthedayofimplantationitself.Bleedingwasmorelikelytooccuraroundthe time women might expect their next period. For 8 of the 14pregnancies, bleedingstartedbetweencycledays27and31(themost commoncyclelengthsinour study). Thisimpliesthatbleedingmaybemorecommonatcertainstagesofearlypregnancy. Curiously, this pattern did not hold when we lookedTableI. Descriptionofearlypregnancystudyparticipantsn %Age2125 32 142630 127 573135 51 233642 11 5RaceWhite 212 96Non-white 9 4Education12 17 81315 46 2116 84 38>17 74 33Graviditya0 78 351 77 352 43 203+ 22 10Outcomeofmostrecentpregnancylivebirth 94 66inducedabortion 25 18spontaneousabortion 16 11stillbirth 4 3molarpregnancy 2 1ectopicpregnancy 1 1aDataunavailable forone womanFigure 1.Datafrom14 clinicalpregnancieswithbleedinginearlypregnancy.Eachlinerepresentsapregnancy.Digitsonthelineshowthenumberofpadsortamponsforvaginalbleedingusedon thatday;`S'is forspottingwithoutpadsortampons.Thesmallopencircleatthebeginningofeachlineindicatesdayofimplantation.Asolidcircleattheendofthelinemarksthepregnanciesendinginspontaneousabortion.The`X's'alongthex-axisshowthe frequencydistributionofdayofbleedingonset.Bleedinginveryearlypregnancy1945 by guest on June 9, 2015http://humrep.oxfordjournals.org/Downloaded from more carefully at bleeding relative to ovulation (the presumedtimeofconception).Inourdata,onlyveofthese14womenhadtheironsetofbleeding1216daysafterovulation, whenmenses most commonly occurs (Baird et al., 1995). Moregenerally, in examining pregnancies by time since conception,we found no stage of development at which bleeding appearedTableII. Potentialriskfactorsforbleedinginearlypregnancyamong151clinicalpregnanciesOverall No.withbleeding%withbleedingP-valuePregnancyoutcomeLivebirth 136 12 9Miscarriage 15 2 13 0.63Gestationalage