First-Trimester Ultrasound: A Comprehensive Guide

10. Threshold, Discriminatory Zone, and “The New Rules”

James M. Shwayder 

(1)

Department of Obstetrics and Gynecology, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216, USA

James M. Shwayder

Email: jshwayder@umc.edu

Keywords

Threshold valueDiscriminatory valueEarly pregnancy failureCrown-rump lengthMean gestational sac sizePregnancy of unknown locationEarly pregnancy evaluation

Introduction

Early pregnancy evaluation markedly improved with the introduction of transvaginal sonography (TVS). Our understanding of early pregnancy growth has increased with improved resolution and imaging capabilities. As a result, a reevaluation of the threshold levels, discriminatory zone, and determination of early pregnancy failure has occurred, with dramatic changes in our recommendations.

Threshold Value

The threshold value is the lowest hCG level at which a normal intrauterine pregnancy (IUP) can be detected. Connolly et al. reevaluated the threshold value in a 2013 manuscript [1]. Previously, threshold values had been reported in the 500–1000 mIU/mL range. Connolly reported a 99 % probability of detecting a gestational sac at 390 mIU/mL (Fig. 10.1). Thus, the diagnosis of a normal IUP can be made earlier than previously assumed. However, this refined capability depends on the sophistication of the ultrasound equipment, the transducer frequency, uterine position, a patient’s body habitus, and the operators experience and ability. Most modern equipment has vaginal probes with appropriate frequencies to detect very early pregnancies. However, a mid-plane uterus or one with numerous myomas may make visualization quite difficult. This author has found that body habitus also impacts the ability to adequately visualize the pelvic anatomy. If an ultrasound study does not resolve or clarify the clinical situation, referral to an expert sonographer with more sophisticated equipment is often of value. Finally, caution is warranted, as these guidelines are not applicable to patients with multiple gestations. This is particularly pertinent in patients who have undergone assisted reproduction.

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Fig. 10.1

Early gestational sac with hCG = 420 mIU/mL

Discriminatory Value

The discriminatory value is that level of hCG above which all normal intrauterine pregnancies should be seen. An early study, using transabdominal ultrasound, advocated a level of 6500 mIU/mL [2]. Clearly, the introduction of transvaginal sonography revolutionized early pregnancy assessment. In 1987, relatively early in the use of TVS, Nyberg et al. reported that the discriminatory level was 1800 mIU/mL (Third International Standard) [3]. As equipment improved the general consensus was that the discriminatory level was between 1000 and 1500 mIU/mL in most centers. This level has become progressively more important with the increased adoption of medical management of ectopic pregnancy. Unfortunately, there are rising numbers of early IUPs being treated with methotrexate, being erroneously diagnosed as an ectopic pregnancy, based on the lack of an intrauterine gestational sac when the hCG is above the discriminatory value. This clearly has both medical and legal implications [4]. The reliance on the previous discriminatory values was contested in a paper by Doubilet and Benson in 2011 [5]. This retrospective review assessed the hCG level in 202 patients evaluated over 10 years, who had a TVS and β-hCG on the same day, had no visualized intrauterine fluid collection on their initial study, but were subsequently found to have an intrauterine pregnancy, with embryonic fetal cardiac activity. They found that 10.4 % of such pregnancies had an hCG > 1500 mIU/mL, with 4.5 % having an hCG above 2000 mIU/mL (Fig. 10.2). This challenged the medical community to reevaluate our current hCG discriminatory level. Connolly et al., in 2013, reported on 651 patients with known intrauterine pregnancies who had a TVS and β-hCG within 6 h of each other. They evaluated the initial ultrasound findings which were visualized 99 % of the time, in correlation with the hCG level (Table 10.1). They determined that the discriminatory value was 3510 mIU/mL, much higher than previously advocated. It is estimated that women with an hCG above 2000 mIU/ML and no visualized gestational sac are more likely to have a nonviable intrauterine pregnancy (65 %) than an ectopic pregnancy (33 %), with the remainder (2 %) being viable intrauterine pregnancies. Thus, in a patient with a pregnancy of unknown location [6], with an hCG level over 2000 mIU/mL and who is hemodynamically stable, observation and follow-up are recommended until the clinical diagnosis is clarified (Fig. 10.3) [78].

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Fig. 10.2

Gestational sac finally visualized when the hCG = 1570 mIU/mL

Table 10.1

Threshold and discriminatory values in 99 % of intrauterine pregnancies [1]

hCG (mIU/mL)

Gestational sac

Yolk sac

Embryo

Threshold value

 390

1094

1394

Discriminatory value

3510

17,716

47,685

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Fig. 10.3

Pregnancy of unknown location with hCG = 3810 mIU/mL. Patient ultimately had IUP with twin gestation

The “New Rules” Regarding Early Pregnancy Failure

Several developmental milestones are observed in normal intrauterine pregnancy, including an intrauterine sac at 5 weeks; a yolk sac at 5.5 weeks, and an embryonic pole and fetal heart activity at 6–6.5 weeks of gestation [910]. Early pregnancy failure was felt to be present when these milestones were not met. However, there is significant interobserver and intraobserver variability (±18.78 %) in measuring the mean sac diameter, and the crown-rump length [11]. As a result, there are recognized limitations of our current definitions of a nonviable pregnancy based on ultrasound evaluation [12]. Abdallah et al. evaluated 1060 women with a diagnosis of an intrauterine pregnancy of unknown viability, of which 473 (44.6 %) remained viable and (55.4 %) nonviable by the 11- to 14-week scan. There was a 4.4 % false-positive rate for a nonviable pregnancy using the traditional cutoff for mean sac diameter (MSD) of 16 mm. This rate dropped to 0.5 % using 20 mm, with no false positives when a MSD of ≥21 mm was used. Considering the inherent variability identified, these authors recommended a cutoff for MSD ≥ 25 mm, a level where no false positives would be encountered (Fig. 10.4). The lack of fetal cardiac activity with a crown-rump length (CRL) = 4 or 5 mm had a false-positive rate of 8.3 %. There were no false-positive results using a CRL cutoff of 5.3 mm. However, considering the identified variability, they recommended using a CRL ≥ 7 mm as the cutoff for determining a nonviable pregnancy (Fig. 10.5). It was recommended that observation with a repeat ultrasound in ~7 days was appropriate in hemodynamically stable patients who did not warrant the more stringent cutoffs identified by their study.

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Fig. 10.4

Anembryonic pregnancy with gestational sac with a mean average diameter of 2.2 cm. No yolk sac or embryo was identified 14 days later

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Fig. 10.5

Nonviable pregnancy. CRL = 12.2 mm, with no cardiac activity on initial evaluation

In 2013, a multispecialty panel on early first trimester pregnancy diagnosis was convened to review the literature and make further recommendations [7]. This panel’s goal was to virtually eliminate false-positive results for early pregnancy failure, thus preventing intervention in early viable intrauterine pregnancies. They had similar findings as Abdallah’s, recommending cutoffs of ≥2.5 cm for MSD without an embryo, and 7.0 mm without embryonic cardiac activity for defining a nonviable pregnancy. In addition, ultrasound findings diagnostic for pregnancy failure included the absence of an embryo with cardiac activity ≥11 days after demonstrating a gestational sac with a yolk sac, or ≥14 days after demonstrating a gestational sac without a yolk sac (Table 10.2; Fig. 10.6). They also established criteria that were suspicious, but not diagnostic, of a failed pregnancy (Table 10.3).

Table 10.2

Ultrasound findings diagnostic of pregnancy failure [7]

• Crown-rump length of ≥7 mm without cardiac activity

• Mean sac diameter of ≥25 mm without an embryo

• Absence of embryonic cardiac activity ≥11 days after an ultrasound showing a gestational sac with a yolk sac

• Absence of embryonic cardiac activity ≥14 days after an ultrasound showing a gestational sac without a yolk sac

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Fig. 10.6

Embryo (arrow) with cardiac activity visualized 10 days after visualizing a yolk sac with no embryo

Table 10.3

Ultrasound findings suspicious for pregnancy failure [7]

• Crown-rump length of <7 mm without cardiac activity

• Mean sac diameter of 16–24 mm without an embryo

• Absence of embryonic cardiac activity 7–10 days after an ultrasound showing a gestational sac with a yolk sac

• Absence of embryonic cardiac activity 7–13 days after an ultrasound showing a gestational sac without a yolk sac

• Absence of an embryo >6 weeks after a sure last menstrual period

• Empty amnion with no visible embryo

• Enlarged yolk sac (>7 mm)

• Small gestational sac in relation to the size of the embryo

– Defined as <5 mm difference between the MSD and the CRL

Summary

Transvaginal sonography has remarkable improved our assessment of early pregnancy. Recent studies have altered our understanding of the ultrasound findings associated with early intrauterine pregnancies, as well as early pregnancy failure. Adopting these revised guidelines will reduce inappropriate treatment of early intrauterine pregnancies with methotrexate, and avoid intervening on early intrauterine pregnancies destined for viability.

Teaching Points

·               The threshold hCG value for initial visualization of an intrauterine pregnancy ranges between 390 and 1000 mIU/mL.

·               The discriminatory value (that level where all intrauterine pregnancies should have an identifiable gestational sac) in identifying an intrauterine pregnancy is higher than previously advocated. It is recommended to raise the discriminatory level of hCG to at least 3000 mIU/ml.

·               The discriminatory level of hCG is higher with multiple pregnancies. Thus, additional caution should be exercised in patients who have undergone assisted reproduction to conceive.

·               Findings that confirm pregnancy failure include:

·                      The lack of a fetal heartbeat with a crown-rump length ≥7 mm.

·                      A mean sac diameter of ≥25 mm with no embryo.

·                      Absence of an embryo with a heartbeat ≥2 weeks after an ultrasound revealed a gestational sac without a yolk sac.

·                      Absence of an embryo with a heartbeat ≥11 days after an ultrasound revealed a gestational sac with a yolk sac.

References

1.

Connolly A, Ryan DH, Stuebe AM, Wolfe HM. Reevaluation of discriminatory and threshold levels for serum β-hCG in early pregnancy. Obstet Gynecol. 2013;121(1):65–70. doi:10.1097/AOG.0b013e318278f421.PubMed

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Nyberg DA, Mack LA, Laing FC, Patten RM. Distinguishing normal from abnormal gestational sac growth in early pregnancy. J Ultrasound Med. 1987;6(1):23–7.PubMed

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Barnhart K, van Mello NM, Bourne T, Kirk E, Van Calster B, Bottomley C, et al. Pregnancy of unknown location: a consensus statement of nomenclature, definitions, and outcome. Fertil Steril. 2011;95(3):857–66.PubMedCentralCrossRefPubMed

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Doubilet PM, Benson CB, Bourne T, Blaivas M. Diagnostic criteria for nonviable pregnancy early in the first trimester. N Engl J Med. 2013;15:1443–51.

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Pexsters A, Luts J, Van Schoubroeck D, Bottomley C, Van Calster B, Van Huffel S, et al. Clinical implications of intra- and interobserver reproducibility of transvaginal sonographic measurement of gestational sac and crown–rump length at 6–9 weeks' gestation. Ultrasound Obstet Gynecol. 2011;38(5):510–5.CrossRefPubMed

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Abdallah Y, Daemen A, Kirk E, Pexsters A, Naji O, Stalder C, et al. Limitations of current definitions of miscarriage using mean gestational sac diameter and crown–rump length measurements: a multicenter observational study. Ultrasound Obstet Gynecol. 2011;38(5):497–502.CrossRefPubMed