Pregnancy of Unknown Location image

Pregnancy of Unknown Location


  • Have a high index of suspicion for ectopic pregnancy in any premenopausal woman with abnormal uterine bleeding and pain
  • Pregnancy of unknown location requires follow up and a diagnosis
  • If patient is clinically stable and pregnancy is desired
    • Repeat transvaginal ultrasound and/or serial measurement of quantitative hCG (qHCG)
  • If patient is clinically unstable, surgical management is warranted (uterine aspiration, laparoscopy, and /or laparotomy)
  • The goal of diagnosing an ectopic pregnancy is to make the determination before rupture, allowing conservative, medical treatment
    • Obtain blood type and Rh status on all women suspected of ectopic pregnancy and all Rh-negative women with bleeding should receive anti-D immune globulin (RhoGam), regardless of the final outcome of the pregnancy
    • Choice of uterine aspiration for diagnosis should be based on shared decision making


  • Pregnancy of unknown location is defined as a pregnancy where intrauterine or ectopic location cannot be confirmed
  • Over 90% of ectopic pregnancies are in the fallopian tube; the remainder can occur in the cervix, ovary, uterine cornua, or abdomen.
  • Risk factors for ectopic pregnancy include (ACOG PB 193)
    • Tubal surgery
    • PID
    • Previous ectopic pregnancy (10% with one previous ectopic rising to 25% with ≥2)
    • Infertility
    • Assisted reproductive technologies with multiple embryo transfer
    • Previous pelvic/abdominal surgery
    • Age >35 years
    • Smoking
    • Current IUD use

Note: IUDs are associated with fewer ectopics compared to women not using contraception because IUDs are such an effective method of birth control | However, if a woman does become pregnant with an IUD, the risk of an ectopic is approximately 50%


  • Diagnosis of ectopic pregnancy versus failed intrauterine pregnancy depends on the following factors
    • qHCG (beta-hCG) ‘Discriminatory Level’ – the level at which an intrauterine gestation can be seen via transvaginal ultrasound with a skilled sonographer
    • Levels are specific to sonographers and equipment but generally are set between qHCG of 1500-3500

qHCG Discriminatory Level

  • Absence of gestational sac in the uterus above ‘discriminatory level’ has a PPV of 50 to 70% (based on a higher range qHCG level of 3500)
  • Multiple gestation may have higher qHCG levels (>2,000 mIU/mL) before ultrasound evidence of pregnancy is visible
  • Large fibroids can obscure an intrauterine gestation
  • Even with a value of 4000 mIU/mL, 5.6% of women had an early IUP that wasn’t detected on ultrasound (Barnhart et al. Fertil Steril, 2015)

Trending qHCG Levels

  • Gestational sac with yolk sac in the uterus is normally visible between 5 to 6 weeks
  • Nondiagnostic transvaginal ultrasound: Fails to show a gestational sac with yolk sac in the uterus or the adnexa
    • Measure qHCG and then repeat it in 48 hours
    • Repeat again every 2 to 7 days based on level/pattern of qHCG results
    • Higher the initial level, slower the expected rate of increase
  • Expected qHCG rate increase (based on 99%ile rates, 99% of women with normal IUP will have a rise at this rate or faster [Barnhart et al. Obstet Gynecol, 2016])
    • <1,500 mIU/mL: 49% increase rate
    • 1,500 to 3,000 mIU/mL: 40% increase rate
    • >3,000 mIU/mL: 33% increase rate
  • An increase in qHCG  <50% in 48 hours in an early pregnancy is very concerning but cannot determine location, i.e., ectopic vs intrauterine
    • 1% of patients with early viable pregnancies may not meet minimal increase thresholds in 48 hours

Transvaginal Ultrasound (TVUS)

  • With ectopic pregnancy, fluid in the uterus mimicking a gestational sac, called a “pseudosac”
    • For diagnosis of intrauterine pregnancy need to see double decidual sign or yolk sac on ultrasound
  • Mass or hypoechoic area separate from the ovary is ‘suspicious’ but not diagnostic
    • PPV is only 80%
    • May be confused with paratubal cyst, corpus luteum, hydrosalpinx, endometrioma or bowel
  • Once IUP is confirmed on TVUS, trending qHCG is no longer useful or diagnostic for success or failure of IUP
  • Some IUP milestones
    • Yolk sac should be visualized by a gestational sac of 1.5cm
    • Fetal pole should be visualized by gestational sac of 2 cm | However, cannot be sure it is a blighted ovum until approximately 4 cm empty sac.
    • Cardiac activity when embryo 1 to 2mm in length
    • Absence of FCA when embryo measures >7mm is diagnostic of pregnancy failure
    • Absent embryo when mean sac diameter ≥25mm is diagnostic of pregnancy failure


  • If TVUS or qHCG is not available, or if clinical picture remains unclear
    • Diagnostic endometrial aspiration to confirm chorionic villi may be necessary
    • Patients should be counseled in advance that this will terminate the pregnancy if intrauterine
    • >15% decrease in qHCG levels between 12- and 24-hours following aspiration suggests that villi have been removed
    • Continue monitoring qHCG until negative and if a plateau or increase, consider non-visualized ectopic pregnancy, especially if villi do not appear in the specimen

Note: See Ectopic pregnancy management chapter (find link in ‘Related Topics’ below) for MTX and surgical management options


Gracia and Barnhart. Obstet Gynecol, 2001

A decision analysis compared multiple algorithms to determine the best approach for diagnosing ectopic pregnancy

  • Data derived from women presenting with abdominal pain or bleeding in their first trimester
  • Results
  • Ideal strategy for diagnosing ectopic pregnancy while minimizing interruption of early IUP was TVUS followed by serial qHCG in those cases where the ultrasound was non-diagnostic
  • Only 1% of IUPs were interrupted and average time to diagnosis was 1.46 days. 
  • Progesterone did not prove to be a useful marker in this analysis as it was not specific for pregnancy location.

Seeber et al. Fertil Steril, 2006

  • Publication that provides qHCG curves derived from a large cohort of patients to determine the validity of the curves and time to diagnosis
  • Results
    • By using the rate of change between 2 consecutive qHCG values vs a minimal rise of 35% (IUP curve) or minimal drop of 21 to 35% (SAB curve) the researchers were able to diagnose an ectopic pregnancy on average 2.5 days earlier than by standard clinical practice at the time 
    • 12% of ectopic cases were diagnosed later, as the initial rise mimicked a normal pregnancy



  • ACOG recommends that

A pregnancy of unknown location should not be considered a diagnosis, rather it should be treated as a transient state and efforts should be made to establish a definitive diagnosis when possible

A woman with a pregnancy of unknown location who is clinically stable and has a desire to continue the pregnancy, if intrauterine, should have a repeat transvaginal ultrasound examination, or serial measurement of hCG concentration, or both, to confirm the diagnosis and guide management 


Diagnosing ectopic pregnancy and current concepts in the management of pregnancy of unknown location (Kirk et al. Hum Reprod Update, 2014)

Diagnosing ectopic pregnancy and current concepts in the management of pregnancy of unknown location

ACOG Practice Bulletin 193: Tubal Ectopic Pregnancy 

Don’t discriminate: even a discriminatory zone as high as 4000 can result in interruption of an IUP (Barnhart et al. Fertil Steril, 2015)

Differences in Serum Human Chorionic Gonadotropin Rise in Early Pregnancy by Race and Value at Presentation (Barnhart et al. Obstet Gynecol, 2016)

RCOG Scientific Impact Paper 58: Diagnostic Biomarkers for Predicting Adverse Early Pregnancy Outcomes

Nice guideline 126: Ectopic pregnancy and miscarriage: diagnosis and initial management

ASRM: Medical treatment of ectopic pregnancy: a committee opinion

Imaging of Acute Pelvic Pain: Pregnant (Ectopic and First-trimester Viability Updated)

Diagnosing Ectopic Pregnancy: Decision Analysis Comparing Six Strategies (Gracia and Barnhart. Obstet Gynecol, 2001)

Application of redefined human chorionic gonadotropin curves for the diagnosis of women at risk for ectopic pregnancy (Seeber et al. Fertil Steril, 2006)