Diagnostic Criteria for Nonviable Pregnancy Early in the First Trimester

T h e n e w e ngl a nd j o u r na l o f m e dic i n eTable 1. Terminology and Diagnostic Tests Used Early in the First Trimester of Pregnancy.TerminologyViableNonviableIntrauterine pregnancyof uncertain viabilityPregnancy of unknown locationDiagnostic testsHuman chorionic gonadotropin(hCG)Pelvic ultrasonography†CommentsA pregnancy is viable if it can potentially result in a liveborn baby.A pregnancy is nonviable if it cannot possibly result in a liveborn baby. Ectopicpregnancies and failed intrauterine pregnancies are nonviable.A woman is considered to have an intrauterine pregnancy of uncertain viabilityif transvaginal ultrasonography shows an intrauterine gestational sac withno embryonic heartbeat (and no findings of definite pregnancy failure).*A woman is considered to have a pregnancy of unknown location if she has apositive urine or serum pregnancy test and no intrauterine or ectopic pregnancyis seen on transvaginal ultrasonography.Serum hCG concentration is measured with the use of the World HealthOrganization 3rd or 4th International Standard.A positive serum pregnancy test is defined by a serum hCG concentration abovea positivity threshold (5 mIU/ml).Minimum quality criteria include transvaginal assessment of the uterus andadnexa and transabdominal evaluation for free intraperitoneal fluid and amass high in the pelvis; oversight provided by an appropriately trained physician;scans performed by providers and interpreted by physicians, all ofwhom meet at least minimum training or certification standards for ultrasonography,including transvaginal ultrasonography; and scanning equipmentpermitting adequate visualization of structures early in the first trimester.* In a woman with a positive urine or serum pregnancy test, an intrauterine fluid collection with rounded edges containingno yolk sac or embryo is most likely a gestational sac; it is certain to be a gestational sac if it contains a yolk sac orembryo.† Transabdominal imaging without transvaginal scanning may be sufficient for diagnosing early pregnancy failure whenan embryo whose crown–rump length is 15 mm or more has no visible cardiac activity.negative diagnosis — failing to diagnose a pregnancyas nonviable. For either an intrauterinepregnancy of uncertain viability or a pregnancyof unknown location, the consequence of a falsepositive diagnosis of nonviability may be dire:medical or surgical intervention that eliminatesor severely damages a viable pregnancy. This ismuch worse than the consequence of a falsenegative diagnosis in women with an intrauterinepregnancy of uncertain viability: a delay (usuallyby a few days) in intervention for a failed pregnancy.Likewise, for a pregnancy of unknownlocation, harming a potentially normal intrauterinepregnancy is considerably worse than thepossible consequence of a false negative diagnosis:a short delay in treatment of an ectopic pregnancyin a woman who is being followed medicallyand has no ultrasonographically identifiableadnexal mass.Thus, the criteria for diagnosing nonviabilityin early pregnancy should virtually eliminatefalse positive results. That is, the goal is a specificityof 100%, which yields a positive predictivevalue of 100% for nonviability, regardless of theprior probability of that diagnosis. We recognizethat this goal cannot always be achieved inclinical practice because of the dependence ofultra sonography on the expertise of the operatorand because of statistical limitations inruling out very rare events. However, we areconfident that current data allow us to achievea specificity extremely close to 100%. Althoughit would be ideal to have both high sensitivityand high specificity, diagnosis of early pregnancyfailure requires a focus on the latter atthe expense of the former. 4,9Research in the past 2 to 3 years 10-12 has shownthat previously accepted criteria for ruling out aviable pregnancy, which were based on smallnumbers of patients, 9 are not stringent enoughto avoid false positive test results. Disseminationof this new information to practitioners and theachievement of standardized practice protocolsare challenging, because the diagnosis and managementof early-pregnancy complications involvephysicians from multiple specialties, includingradiology, obstetrics and gynecology, emergencymedicine, and family medicine. As a result, there1444n engl j med 369;15 nejm.org october 10, 2013The New England Journal of MedicineDownloaded from nejm.org on October 10, 2013. For personal use only. No other uses without permission.Copyright © 2013 Massachusetts Medical Society. All rights reserved.

current conceptsAB19.1 mm+ +Figure 1. Early Intrauterine Gestational Sac.A transvaginal ultrasonogram obtained at 5 weeks of gestation (Panel A) shows a small, round, fluid­filled structure(arrow), which was confirmed to be an early intrauterine pregnancy 4 weeks later (Panel B) on a follow­up scan showinga fetus measuring 19.1 mm, corresponding to approximately 9 weeks of gestational age. Plus signs indicate calipers.is a patchwork of sometimes conflicting, oftenoutdated published recommendations and guidelinesfrom professional societies. 13In this review, we examine the diagnosis ofnonviability in early intrauterine pregnancy ofuncertain viability and in early pregnancy of unknownlocation separately, focusing mainly onthe initial (or only) ultrasonographic study performedduring the pregnancy. Our recommendationsare meant to apply to any practice, subspecialtyor community-based, that meets at leastthe minimum quality criteria for pelvic ultrasonographylisted in Table 1.Di agnosing Pr egna nc y Fa ilur ein a n In tr au ter ine Pr egna nc yof Uncerta in V i a bilit yThe sequence of events in early pregnancy, as seenon transvaginal ultrasonography, follows a fairlypredictable pattern. The gestational sac is first seenat approximately 5 weeks of gestational age, 14,15appearing as a small cystic-fluid collection withrounded edges and no visible contents, located inthe central echogenic portion of the uter us (i.e.,within the decidua). Previously described ultrasonographicsigns of early pregnancy — the“double sac sign” 16 and “intradecidual sign” 17— were defined with the use of transabdominalultrasonography, but with current transvaginalultrasono graphic technology, these signs are absentin at least 35% of gestational sacs. 18 Therefore,any round or oval fluid collection in awoman with a positive pregnancy test mostlikely represents an intrauterine gestational sac(Fig. 1) 19,20 and should be reported as such; it ismuch less likely to be a pseudogestational sacor decidual cyst, findings that can be present ina woman with an ectopic pregnancy. 21,22The yolk sac, a circular structure about 3 to5 mm in diameter, makes its appearance atabout 5 1 ∕2 weeks of gestation. The embryo is firstseen adjacent to the yolk sac at about 6 weeks, atwhich time the heartbeat is present as a flickeringmotion. 14,15Variations from the expected pattern of developmentare worrisome or, if major, definitive forearly pregnancy failure. The criteria most oftenused to diagnose pregnancy failure are the absenceof cardiac activity by the time the embryohas reached a certain length (crown–rump length),the absence of a visible embryo by the time thegestational sac has grown to a certain size (meansac diameter), and the absence of a visible embryoby a certain point in time.Crown–Rump Length as a Criterionfor Failed PregnancyShortly after transvaginal ultrasonography becamewidely available in the mid-to-late 1980s,n engl j med 369;15 nejm.org october 10, 2013 1445The New England Journal of MedicineDownloaded from nejm.org on October 10, 2013. For personal use only. No other uses without permission.Copyright © 2013 Massachusetts Medical Society. All rights reserved.

T h e n e w e ngl a nd j o u r na l o f m e dic i n eTable 2. Guidelines for Transvaginal Ultrasonographic Diagnosis of Pregnancy Failure in a Woman with an IntrauterinePregnancy of Uncertain Viability.*Findings Diagnostic of Pregnancy FailureCrown–rump length of ≥7 mm and no heartbeatMean sac diameter of ≥25 mm and no embryoAbsence of embryo with heartbeat ≥2 wk after a scanthat showed a gestational sac without a yolk sacAbsence of embryo with heartbeat ≥11 days after ascan that showed a gestational sac with a yolk sacFindings Suspicious for, but Not Diagnostic of, Pregnancy Failure†Crown–rump length of 7 mm)Small gestational sac in relation to the size of the embryo (

T h e n e w e ngl a nd j o u r na l o f m e dic i n epregnancies. 10,35 In addition, the inter observervariation in the measurement of the mean sacdiameter is ±19%, 32 so a diameter of 21 mm (theupper limit above) as measured by one observermay be 19% greater, or 25 mm, when measuredby another observer.These studies, in combination, suggest that itis prudent to use a cutoff of 25 mm (rather than16 mm) for the mean sac diameter with no visibleembryo (Table 2) in diagnosing failed pregnancy(Fig. 2B and 2C). This would yield a specificityand positive predictive value of 100% (or as closeto 100% as can be determined). When the meansac diameter is 16 to 24 mm, the lack of an embryois suspicious for, though not diagnostic of,failed pregnancy (Fig. S2 in the SupplementaryAppendix).Time-based Criteria for Failed PregnancyNot all failed pregnancies ever develop a 7-mmembryo or a 25-mm gestational sac, so it is importantto have other criteria for diagnosingpregnancy failure. The most useful of such criteriainvolve nonvisualization of an embryo by acertain point in time. An alternative approach topredicting pregnancy failure, based on subnormalgrowth of the gestational sac and embryo,has been shown to be unreliable. 36Nonvisualization of an embryo with a heartbeatby 6 weeks after the last menstrual periodis suspicious for failed pregnancy, but dating ofthe last menstrual period (in a pregnancy conceivedwithout medical assistance) is too unreliablefor definitive diagnosis of pregnancy failure.37 The timing of events in early pregnancy— gestational sac at 5 weeks, yolk sac at 5 1 ∕2weeks, and embryo with heartbeat at 6 weeks— is accurate and reproducible, with a variationof about ± 1 ∕2 week 14,15 ; this consistency explainsthe time-related criteria for pregnancy failurelisted in Table 2. For example, if the initial ultrasonogramshows a gestational sac with a yolk sacand a follow-up scan obtained at least 11 dayslater does not show an embryo with cardiac activity,the diagnosis of failed pregnancy is established(Fig. 2D and 2E; also see Fig. S3 in theSupplementary Appendix).Other Suspicious FindingsSeveral ultrasonographic findings early in thefirst trimester have been reported as abnormal.These include an “empty” amnion, 38 an enlargedyolk sac, 39 and a small gestational sac. 40 Criteriafor these abnormal findings are presented inTable 2. Because none of these signs have beenextensively studied, they are considered to besuspicious for, though not diagnostic of, failedpregnancy.Di agnosing a nd Ruling Ou ta V iable Intr auter ine Pr egnancyin a Woman with a Pregnancyof Unknown LocationThe evaluation and management of a pregnancyof unknown location have received considerableattention, with various flow charts and mathematicalmodels proposed for use in this context.41,42 Our intent here is not to review thebroad topic of pregnancy of unknown location,but instead to focus on one important element:the role of an hCG level at a single point in timein diagnosing or ruling out a viable intrauterinepregnancy and in guiding patient-care decisions.The hCG levels in viable intrauterine pregnancies,nonviable intrauterine pregnancies, andectopic pregnancies have considerable overlap,so a single hCG measurement does not distinguishreliably among them. 2,4,43 Considerableresearch during the past 30 years has sought todetermine the discriminatory hCG level: thevalue above which an intrauterine gestationalsac is consistently seen on ultra sonography innormal pregnancies. An early study, based ontransabdominal ultrasonography, put the level at6500 mIU per milliliter. 44 With improvements inultrasonographic technology, including the introductionof transvaginal ultrasonography, gestationalsacs became detectable earlier in pregnancy,and the reported discriminatory hCGlevel was brought down to 1000 to 2000 mIU permilliliter. 45-47 As with the crown–rump lengthand mean sac diameter, however, more recentresearch has shown that previously acceptedvalues for the discriminatory hCG level are notas reliable for ruling out a viable pregnancy asoriginally thought.One reason for the lower reliability of thediscriminatory hCG level today than was reportedin the past may be the fact that multiplegestations, which are associated with higherhCG levels at a given stage of pregnancy thanare singleton gestations, are more commonnow than they were 20 to 30 years ago. Failureof the discriminatory hCG level to rule out aviable intrauterine pregnancy, however, has1448n engl j med 369;15 nejm.org october 10, 2013The New England Journal of MedicineDownloaded from nejm.org on October 10, 2013. For personal use only. No other uses without permission.Copyright © 2013 Massachusetts Medical Society. All rights reserved.

current conceptsbeen seen in singleton as well as multiple gestations.Several studies have documented casesin which an embryo with cardiac activity wasseen on follow-up ultrasonography after initialultrasonography showed no gestational sac withan hCG level above 2000 mIU per milliliter 12,48,49and even above 3000 mIU per milliliter. 12,48In a woman with a pregnancy of unknownlocation whose hCG level is more than 2000 mIUper milliliter, the most likely diagnosis is a nonviableintrauterine pregnancy, occurring approximatelytwice as often as ectopic pregnancy. 50Ectopic pregnancy, in turn, occurs approximately19 times as often as a viable intrauterine pregnancywhen the hCG level is 2000 to 3000 mIUper milliliter and the uterus is empty, and 70 timesas often as a viable intrauterine pregnancy whenthe hCG level is more than 3000 mIU per milliliterwith an empty uterus. (These latter estimatesare based on data from one institution assessingectopic pregnancies 19 and viable intrauterinepreg nancies 12 in relation to hCG levels in womenwith an empty uterus.)On the basis of these values, among womenwith a pregnancy of unknown location and hCGlevels of 2000 to 3000 mIU per milli liter, therewill be 19 ectopic pregnancies and 38 nonviableintrauterine pregnancies for each viable intrauterinepregnancy. Thus, the like lihood of a viableintrauterine pregnancy for such women is[1 ÷ (1 + 19 + 38)], or approximately 2%. If we usethe same reasoning for women with a pregnancyof unknown location and hCG levels ofmore than 3000 mIU per milliliter, the likelihoodof a viable intrauterine pregnancy is[1 ÷ (1 + 70 + 140)], or approximately 0.5%.We recognize that these estimates of the likelihoodof a viable intrauterine pregnancy in awoman with a pregnancy of unknown locationwhose hCG level is 2000 mIU per milliliter orhigher are not highly precise, given the limitationsof the available data, but there are a numberof reasons why presumptive treatment for ectopicpregnancy with the use of methotrexate or otherpharmacologic or surgical means is inappropriateif the woman is hemodynamically stable.First, as noted above, there is a chance of harminga viable intrauterine pregnancy, especially ifthe hCG level is 2000 to 3000 mIU per milliliter.Second, the most likely diagnosis is nonviableintrauterine pregnancy (i.e., failed pregnancy), 50and methotrexate is not an appropriate treatmentfor a woman with this diagnosis. Third, there islimited risk in taking a few extra days to make adefinitive diagnosis in a woman with a pregnancyof unknown location who has no signs orsymptoms of rupture and no ultrasonographicevidence of ectopic pregnancy. Fourth, the progressionof hCG values over a period of 48 hoursprovides valuable information for diagnostic andtherapeutic decision making. 4,51 Thus, it is generallyappropriate to do additional testing beforeundertaking treatment for ectopic pregnancy in ahemodynamically stable patient (Table 3). 2,43,52Table 3. Diagnostic and Management Guidelines Related to the Possibility of a Viable Intrauterine Pregnancyin a Woman with a Pregnancy of Unknown Location.*FindingNo intrauterine fluid collectionand normal (or near-normal)adnexa on ultrasonography†Ultrasonography not yetperformedKey PointsA single measurement of hCG, regardless of its value, does not reliably distinguishbetween ectopic and intrauterine pregnancy (viable or nonviable).If a single hCG measurement is

T h e n e w e ngl a nd j o u r na l o f m e dic i n eWomen with ectopic pregnancies have highlyvariable hCG levels, often less than 1000 mIUper milliliter, 43,53,54 and the hCG level does notpredict the likelihood of ectopic pregnancy rupture.55 That is, a single hCG value, even if low,does not rule out a potentially life-threateningruptured ectopic pregnancy. Hence, ultrasonographyis indicated in any woman with a positivepregnancy test who is clinically suspected ofhaving an ectopic pregnancy.ConclusionsA false positive diagnosis of nonviable pregnancyearly in the first trimester — incorrectly diagnosingpregnancy failure in a woman with an intrauterinegestational sac or ruling out viable intrauterinegestation in a woman with a pregnancy of unknownlocation — can prompt interventions thatdamage a pregnancy that might have had a normaloutcome. Recent research has shown the needto adopt more stringent criteria for the diagnosisof nonviability in order to minimize or avoid falsepositive test results. The guidelines presented here,if promulgated widely to practitioners in the variousspecialties involved in the diagnosis and managementof problems in early pregnancy, wouldimprove patient care and reduce the risk of inadvertentharm to potentially normal pregnancies.Supported by funding from the National Institute for HealthResearch Biomedical Research Centre based at Imperial CollegeHealthcare National Health Service Trust and Imperial CollegeLondon (to Dr. Bourne).Dr. Benacerraf reports receiving lecture fees from World ClassCME and the International Institute for Continuing Medical Educationand travel reimbursement from GE Healthcare. Dr. Bensonreports receiving fees for expert testimony in medical malpracticecases regarding standard of care for interpretation of ultrasonographicexaminations and lecture fees from the International Institutefor Continuing Medical Education and the Institute forAdvanced Medical Education. Dr. Doubilet reports receiving feesfor expert testimony in medical malpractice cases regarding standardof care for interpretation of ultrasonographic examinationsand lecture fees from the International Institute for ContinuingMedical Education. Dr. Filly reports receiving fees for expert testimonyin medical malpractice cases as an expert in diagnostic sonographyand lecture fees from World Class CME. He also reportsbeing co-holder of a patent for a needle-guide device used forvenous access under ultrasonographic guidance. Dr. Goldsteinreports receiving consulting fees from Cook OB/GYN, Pfizer,Shionogi, and Bayer and lecture fees from Merck and WarnerChilcott. Dr. Lyons reports receiving lecture fees from GE MedicalSystems and holding stock in Zonare Medical Systems. No otherpotential conflict of interest relevant to this article was reported.Disclosure forms provided by the authors are available withthe full text of this article at NEJM.org.References1. Creanga AA, Shapiro-Mendoza CK,Bish CL, Zane S, Berg CJ, Callaghan WM.Trends in ectopic pregnancy mortality inthe United States, 1980-2007. Obstet Gynecol2011;117:837-43.2. Barnhart KT. Ectopic pregnancy.N Engl J Med 2009;361:379-87.3. Doubilet PM, Benson CB. First, do noharm . . . to early pregnancies. J UltrasoundMed 2010;29:685-9.4. Barnhart KT. Early pregnancy failure:beware of the pitfalls of modern management.Fertil Steril 2012;98:1061-5.5. Nurmohamed L, Moretti ME, SchechterT, et al. Outcome following high-dosemethotrexate in pregnancies misdiagnosedas ectopic. Am J Obstet Gynecol 2011;205(6):533.e1-533.e3.6. Shwayder JM. Waiting for the tide tochange: reducing risk in the turbulent seaof liability. Obstet Gynecol 2010;116:8-15.7. Misdiagnosed ectopic, given methotrexate.Facebook website (http://www.facebook.com/groups/misduagnosedectopic/).8. Doubilet P. A mathematical approachto interpretation and selection of diagnostictests. Med Decis Making 1983;3:177-95.9. Jeve Y, Rana R, Bhide A, ThangaratinamS. Accuracy of first trimester ultrasoundin the diagnosis of early embryonicdemise: a systematic review. UltrasoundObstet Gynecol 2011;38:489-96.10. Abdallah Y, Daemen A, Kirk E, et al.Limitations of current definitions of miscarriageusing mean gestational sac diameterand crown–rump length measurements:a multicenter observational study. UltrasoundObstet Gynecol 2011;38:497-502.11. Hamilton J, Hamilton J. The 6 mmcrown–rump length threshold for detectingfetal heart movements — what is theevidence? Ultrasound Obstet Gynecol 2011;38:Suppl 1:7. abstract.12. Doubilet PM, Benson CB. Further evidenceagainst the reliability of the humanchorionic gonadotropin discriminatorylevel. J Ultrasound Med 2011;30:1637-42.13. Thilaganathan B. The evidence basefor miscarriage diagnosis: better late thannever. Ultrasound Obstet Gynecol 2011;38:487-8.14. Bree RL, Edwards M, Böhm-Velez M,Beyler S, Roberts J, Mendelson EB. Transvaginalsonography in the evaluation ofnormal early pregnancy: correlation withhCG level. AJR Am J Roentgenol 1989;153:75-9.15. Goldstein I, Zimmer EA, Tamir A,Peretz BA, Paldi E. Evaluation of normalgestational sac growth: appearance ofembryonic heartbeat and embryo bodymovements using the transvaginal technique.Obstet Gynecol 1991;77:885-8.16. Bradley WG, Fiske CE, Filly RA. Thedouble sac sign of early intrauterine pregnancy:use in exclusion of ectopic pregnancy.Radiology 1982;143:223-6.17. Yeh H-C, Goodman JD, Carr L, RabinowitzJG. Intradecidual sign: a US criterionof early intrauterine pregnancy. Radiology1986;161:463-7.18. Doubilet PM, Benson CB. 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Endovaginal ultrasound: demonstrationof cardiac activity in embryos ofless than 5.0 mm in crown-rump length.Radiology 1990;176:71-4.1450n engl j med 369;15 nejm.org october 10, 2013The New England Journal of MedicineDownloaded from nejm.org on October 10, 2013. For personal use only. No other uses without permission.Copyright © 2013 Massachusetts Medical Society. All rights reserved.