When a pregnancy fails early

From the start, pregnancy poses significant risk to a woman’s health, and differentiating normal from abnormal gestation may be challenging for a clinician. The time from a positive urine pregnancy test (UPT) to a confirmed viable pregnancy can be a few weeks, during which there can be cramping, spotting, and lack of early pregnancy signs, all of which may lead to anxiety for a patient.

The major goal for the clinician is to confirm the location and viability of the pregnancy. Diagnosing a normal intrauterine, an abnormal intrauterine, or abnormally located pregnancy may be complicated and is integral for management of pregnancy. Certain conditions (eg, ectopic pregnancy, molar pregnancy) can not only fail to result in a live birth but also impose significant maternal morbidity and mortality unless treated promptly. The term early pregnancy loss or failure (EPF) refers to a non-viable, intrauterine pregnancy with either an empty gestational sac or a gestational sac containing an embryo or fetus without heart activity within the first 12 6/7 weeks of gestation.¹ At the same time premature assumption of the non-viability of a pregnancy can result in over-diagnosis of EPF and irreversible treatment measures in cases of very early but potentially viable pregnancies. That can be detrimental when the pregnancy is desired. Since falsely diagnosing a pregnancy as failed carries potentially more harmful consequences than delay in diagnosing a failed pregnancy, the specificity goal for the criteria for the diagnosis of non-viability is 100%.² The formulation of this goal in the context of several large multicenter studies necessitated challenging the prior diagnostic cutoffs and timelines. The consequence was a recent change in guidelines for diagnosis of EPF, which on one hand made the criteria more strictly outlined and, on the other hand, allowed for longer waiting time prior to making the final determination of non-viability.^3,4 Here we review the current guidelines and available literature on early pregnancy diagnosis (up to 12 6/7 weeks’ gestation), localization and identification of viability as well as management options and counseling.

Pregnancy diagnosis

In most cases, the diagnosis of pregnancy is made with a positive pregnancy test (using urine or blood) in a reproductive-age women. This may be done when a woman is anticipating a pregnancy or she develops normal pregnancy-related symptoms (such as amenorrhea, nausea and vomiting, and breast tenderness) or abnormal pregnancy-related symptoms (unusual vaginal bleeding, back or lower abdominal pain) or even signs of clinical instability (life-threatening vaginal bleeding, syncopal episode, etc.).

Human chorionic gonadotropin

The pregnancy test in current use is based on detection of human chorionic gonadotropin (hCG) in a woman’s urine or blood. hCG is a 237 aminoacid glycoprotein hormone produced largely by syncytiotrophoblast cells and composed of alpha and beta subunits. Its main function is to stimulate progesterone production by the corpus luteum until approximately 14 weeks’ gestation. In normal singleton pregnancy hCG starts to rise as early as 6–12 days after ovulation and reaches its peak of 100,000 at ~10 weeks’ gestation, after which it slowly decreases to a plateau of 20,000 mIU/mL in the mid-second trimester, where it stays until delivery.^5,6

Although beta hCG is the predominant form of hCG in the urine of pregnant women, home pregnancy tests are designed to detect both hCG and beta hCG. The sensitivity of over-the-counter tests varies greatly among brands and ranges from 0.4 to 6.3 IU/L (despite manufacturer-claimed sensitivity of 25 IU/L).⁸

Most serum assays are now designed to measure hCG and hCG-beta equally. The sensitivities of current quantitative pregnancy tests are ~25 IU/L and 1 IU/L for enzyme-linked assays and fluoroimmunoassays, respectively. The upper limit of the reference range is ~3 IU/L in non-pregnant women <50 years old and ~5.4 IU/L in women >50 years old.⁹

Ultrasound evaluation of early pregnancy

Use of ultrasound (U/S) in obstetrics and gynecology dates back to 1958 when Donald et al. published their experience on identification of abdominal masses using U/S in the Lancet.¹⁰ Since then U/S evaluation has become nearly universal in developed countries as part of routine prenatal care and is used to diagnose pregnancy, establish its location and viability, and assess fetal anatomy and growth and placental position. Ultrasound has become a preferred modality for pregnancy viability assessment since 1987 when the transvaginal approach for this purpose became widely available.^11,12 Since then criteria for a non-viable pregnancy have been suggested.

A pregnancy is termed viable if it has the potential to result in a live-born neonate.^2,12 The two major criteria that must be met for a pregnancy to be viable are a normally location within the uterus and a potentially viable fetus.

Location

Timely identification of a pregnancy’s normal location within the uterus is crucial. The diagnosis of intrauterine pregnancy is most commonly made with U/S, based on identification of an intrauterine gestational sac located toward the fundus with at least yolk sac or fetal pole with or without a heartbeat (Figure 1).
 

Findings of gestational sac but without yolk sac or fetal pole traditionally were not considered exclusive of abnormally located pregnancy due to a possibility of the visualized sac being a pseudosac in association with an ectopic pregnancy. This paradigm and thus the term pseudosac itself, however, have recently been challenged due to the predominance of occasions when a round fluid collection in the uterus in conjunction with a positive pregnancy test were indicative of an intrauterine pregnancy.^13,14

Viability

Criteria for viability can vary at different gestational ages. In a viable singleton pregnancy, correlation between pregnancy dating, hCG level, and U/S findings has been described, though there is some variability in the milestones. The embryo is expected to grow by at least 0.2 mm/day, and the gestational sac at least 1 mm/day.¹⁵
 

In many instances a single point hCG measurement is not diagnostic of either the viability of pregnancy, or its location; rather hCG trend is much more helpful in distinguishing those. With a normal intrauterine pregnancy hCG is expected to rise by at least 53% over a 48-hour period, and a deviation from that trend may indicate a nonviable intrauterine or an abnormally located pregnancy. Importantly, observation of a normal rise does not necessarily exclude the possibility of an abnormal intrauterine or abnormally located pregnancy.¹⁸ Once a viable IUP is confirmed, hCG does not need to be trended further. To describe the correlation between the hCG level and U/S findings, the term “discriminatory zone” (Table) emerged and is used to determine the hCG value above which an intrauterine gestational sac is consistently seen on U/S in normal pregnancies.¹³ The discriminatory zone is institution-specific and usually ranges between 1500 and 3500 mIU/mL. However, care should be taken to personalize the use of discriminatory zone because there are certain clinical scenarios that result in deviation of the hCG curve and U/S findings from expected pattern. An example is early multiple-order gestations, which may not necessarily have the same association between the hCG level and U/S findings and higher discriminatory hCG level (~3000 mIU/mL).

Early pregnancy failure

The term “early pregnancy loss” or EPF refers to a nonviable, intrauterine pregnancy with either a gestational sac that is empty or contains an embryo or fetus without heart activity within the first 12 6/7 weeks of gestation. EPF occurs in 15% of all clinically recognized pregnancies and most frequently results from a spontaneous chromosomal abnormality of the embryo. Depending on clinical presentation and U/S findings EPF can be divided into several categories.

• Anembryonic pregnancy, also known as a blighted ovum: this EPF is characterized by no embryo development once a gestational sac reaches 25 mm (Figure 3A).
• Embryonic/fetal death is also known as missed abortion. This is characterized by an IUP with an embryo that either never developed a heartbeat or that previously had a heartbeat, but now lacks one (Figure 3B).
• Spontaneous abortion is characterized by a previously seen IUP, followed by cramping and bleeding. A spontaneous abortion may either be complete, as the uterus expels the products of conception (POCs) on its own, or inevitable, with an open os and gestational sac in the lower uterine segment.

Previous recommendations did not have a 0% false positive rate, and therefore a number of viable pregnancies were destined to be treated as though they were losses. Traditional data on EPF utilized a crown–rump length of 5 mm without cardiac activity, or an empty gestational sac of 16 mm as diagnostic criteria.11,12 Recent prospective studies, however, revealed an 8.3% false-positive rate with this crown–rump length and a 4.4% false-positive rate with this gestational sac diameter. In thoser studies, it was necessary to achieve a 0% false-positive rate, a crown–rump length of 5.3 mm without cardiac activity, or an empty gestational sac of 21 mm. The same group also found that an empty gestational sac 7 days from initial identification of the sac was 100% diagnostic of EPF.1,3,4 In response, the American College of Obstetricians and Gynecologists (ACOG) released in May 2015 an updated Practice Bulletin with diagnostic criteria of EPF incorporating guidelines from the Society of Radiologists in Ultrasound (SRU). The new guidelines allow for diagnosis of EPF in the situations summarized in Table 2 (from AGOG Bulletin #150, May 2015). The new criteria for EPF are less strict, allowing for lengthening of the waiting time prior to EPF diagnosis and thus minimizing the false-positive rate. If the diagnosis is at all in doubt, serial U/S assessment is recommended.

Certain U/S findings can be suggestive of a nonviable pregnancy. To add to the list above, additional findings concerning for EPF are: fetal bradycardia, expanded amnion sign, and yolk sac abnormalities (size >6 mm, abnormal location, number, or echogenicity).^15,19,20 Importantly, both ACOG and the SRU state, “These are the radiologic criteria only and do not replace clinical judgment.” Other factors to account for are the risks of postponing diagnosis in medically complex patients, the patient’s desire to continue the pregnancy, or the patient’s desire to achieve 100% certainty prior to intervention. A discussion with the patient about the possible outcomes should be had, and should guide further diagnostic and clinical management.

Because assigning an estimated date of delivery is frequently challenging due to unknown/inaccurate LMP, most of the criteria in the chart are based on U/S findings and their changes over time rather than on gestational age. Thus the patient should be followed with serial hCG levels, and repeat U/S in 7–14 days. In addition, if no IUP is seen, the diagnosis of pregnancy of unknown location (PUL) is made and the patient should be told of the warning signs for ectopic pregnancy.

Disclosures:

None of the authors report a conflict of interest to report with respect to the content of this article.

References:

• Doubilet PM. Ultrasound evaluation of the first trimester. Radiol Clin North Am, 2014. 52(6):1191-9.
• Doubilet PM, et al. Diagnostic criteria for nonviable pregnancy early in the first trimester. Ultrasound Q, 2014. 30(1):3-9.
• Abdallah Y, et al. Gestational sac and embryonic growth are not useful as criteria to define miscarriage: a multicenter observational study. Ultrasound Obstet Gynecol, 2011. 38(5):503-9.
• Abdallah Y, 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.
• Barnhart KT, et al. Symptomatic patients with an early viable intrauterine pregnancy: HCG curves redefined. Obstet Gynecol, 2004. 104(1):50-5.
• Wilcox AJ. Baird DD, Weinberg CR. Time of implantation of the conceptus and loss of pregnancy. N Engl J Med, 1999. 340(23):1796-9.
• Korevaar TIM, et al.,Reference ranges and determinants of total hCG levels during pregnancy: the Generation R Study. European Journal of Epidemiology, 2015. 30(9):1057-1066.
• Cervinski MA, et al. Qualitative point-of-care and over-the-counter urine hCG devices differentially detect the hCG variants of early pregnancy. Clin Chim Acta, 2009. 406(1-2): 81-5.
• Montagnana M, et al. Human chorionic gonadotropin in pregnancy diagnostics. Clin Chim Acta, 2011. 412(17-18):1515-20.
• Donald I. Clinical application of ultrasonic techniques in obstetrical and gynaecological diagnosis. J Obstet Gynaecol Br Emp, 1962. 69:1036.
• Brown DL, et al.,Diagnosis of early embryonic demise by endovaginal sonography. J Ultrasound Med, 1990. 9(11): p. 631-6.
• Pennell RG, et al. Prospective comparison of vaginal and abdominal sonography in normal early pregnancy. J Ultrasound Med, 1991. 10(2): p. 63-7.
• Doubilet PM, et al. Diagnostic criteria for nonviable pregnancy early in the first trimester. N Engl J Med, 2013. 369(15):1443-51.
• Bradley WG, Fiske CE, Filly RA. The double sac sign of early intrauterine pregnancy: use in exclusion of ectopic pregnancy. Radiology, 1982. 143(1):223-6.
• Hamza A, et al. Diagnostic Methods of Ectopic Pregnancy and Early Pregnancy Loss: a Review of the Literature. Geburtshilfe Frauenheilkd, 2016. 76(4):377-382.
• Goldstein I, et al. Evaluation of normal gestational sac growth: appearance of embryonic heartbeat and embryo body movements using the transvaginal technique. Obstet Gynecol, 1991. 77(6):885-8.
• Bree RL, et al. Transvaginal sonography in the evaluation of normal early pregnancy: correlation with HCG level. AJR Am J Roentgenol, 1989. 153(1):75-9.
• Chung K, Allen R. The use of serial human chorionic gonadotropin levels to establish a viable or a nonviable pregnancy. Semin Reprod Med, 2008. 26(5):383-90.
• Horrow MM. Enlarged amniotic cavity: a new sonographic sign of early embryonic death. AJR Am J Roentgenol, 1992. 158(2):359-62.
• Bromley B, et al. Small sac size in the first trimester: a predictor of poor fetal outcome. Radiology, 1991. 178(2):375-7.