Progesterone levels
A progesterone level often is used to attempt to determine pregnancy viability in women who are not receiving progesterone supplementation, although it ultimately has limited utility. While far less sensitive than an hCG value trend, a serum progesterone level of less than 5 to 10 ng/mL is a rough marker of nonviable pregnancy.23
In a large meta-analysis of women with pain and bleeding, 96.8% of pregnancies with a single progesterone level of less than 10 ng/mL were nonviable.23 When an inconclusive ultrasonography was documented in addition to symptoms of pain and bleeding, 99.2% of pregnancies with a progesterone level of less than 3.2 to 6 ng/mL were nonviable.
Progesterone’s usefulness in assessing for a PUL is limited: While progesterone levels may indicate nonviability, they provide no indication of pregnancy location (intrauterine or ectopic).
Alternative serologic markers
Various other reproductive and pregnancy-related hormones have been investigated for use in the diagnosis of pregnancy location in PULs, including activin A, inhibin A, pregnancy-associated plasma protein A (PAPP-A), placental-like growth factor, vascular endothelial growth factor, follistatin, and various microRNAs.24,25 While research into these biomarkers is ongoing, none have been studied in prospective trials, and they are not for use in current clinical care.
Pelvic ultrasonography
Pelvic ultrasonography is a crucial part of PUL assessment. Transvaginal ultrasonography should be interpreted in the context of the estimated gestational age of the pregnancy and serial hCG values, if available; the patient’s symptoms; and the sensitivity of the ultrasonography equipment, which also may be affected by variables that can reduce visualization, such as uterine fibroids and obesity.
The “discriminatory zone” refers to the hCG value above which an IUP should be visualized by ultrasonography. Generally, with an hCG value of 1,500 to 2,000 mIU/mL or greater, an IUP is expected to be seen with transvaginal sonography.3,26 Many exceptions to the discriminatory zone have been reported, however, including multiple pregnancies, which will have a higher hCG value at an earlier gestational age. Even in singleton pregnancies, viable IUPs have been documented as developing from PULs with an elevated initial hCG value as high as 4,300 mIU/mL.27 The discriminatory zone may vary among clinical hCG assays, and it also is affected by the quality and modernity of the ultrasonography equipment as well as by the ultrasonography operator’s experience and skill.28,29
The estimated gestational age, based on either the last menstrual period or assisted reproduction procedure, provides a helpful data point to guide expectations for ultrasonography findings.30 Using transvaginal ultrasonography in a normally progressing IUP, a gestational sac—typically measuring 2 to 3 mm—should be visualized at 5 weeks.15,30 At approximately 5.5 weeks, a yolk sac measuring 3 to 5 mm should appear. At 6 weeks, an embryo with cardiac activity should be visualized.
In a pregnancy reliably dated beyond 5 weeks, the lack of an intrauterine gestational sac is suspicious for, but not diagnostic of, an EP. Conversely, the visualization of a gestational sac alone (without a yolk sac) is insufficient to definitively exclude an EP, since a small fluid collection in the endometrium (a “pseudosac”) can convincingly mimic the appearance of a gestational sac, and a follow-up ultrasonography should be performed in such cases.
Among patients without ultrasonographic evidence of an IUP, endometrial thickness has been posited as a way to differentiate between IUP and EP.31,32 Evidence suggests that an endometrial stripe of at least 8 to 10 mm may be somewhat predictive of an IUP, while endometrial thickness below 8 mm is more concerning for EP. This clinical variable, however, has been shown repeatedly to lack sufficient sensitivity and specificity for IUP and should be considered only within the entire clinical context.
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