Pregnancies of Uncertain Location or Viability Research
Condition: Intrauterine Pregnancy; Ectopic Pregnancy
MeSH terms: Pregnancy, Ectopic
Study type: Observational

Summary: 
      Study to determine the diagnostic accuracy of the double decidual sac sign to predict an
      intrauterine pregnancy prior to ultrasonographic visualisation of embryonic contents using
      modern ultrasound technology.
    

Detailed description: 
      This diagnostic accuracy study will be conducted following the standards for reporting of
      diagnostic accuracy study (STARD) guidelines. Participants will be recruited from Nurture
      Fertility, Nottingham, United Kingdom at the time of embryo transfer. If the subsequent
      pregnancy test is positive, participants will be invited to attend for an additional
      transvaginal ultrasound scan at 33-34 days gestation. This scan will be considered to be the
      'index test'.

      The index test will be performed by a single investigator with experience in early pregnancy
      ultrasound following standard operating procedures using a Voluson E8 machine with a high
      frequency (5-9MHz and 9-12MHz) transvaginal probe. During the early scan the presence or
      absence of the following structures will be recorded: an intrauterine fluid collection
      (defined as a uniformly round, hypoechoic structure with an echogenic rim); the double
      decidual sac sign (DDSS) (defined as two concentric echogenic rings of tissue that surround
      the intraendometrial fluid collection that impress upon the endometrial stripe); yolk sac
      (defined as a spherical, hyperechoic ring situated eccentrically within the gestation sac);
      and fetal pole (defined as a small linear echogenic structure adjacent to the yolk sac, on
      the side closest to the gestational sac). If more than one intrauterine fluid collection is
      visualized then each will be considered as a separate entity. The findings from the early
      scan will be interpreted immediately and recorded separate to the main clinical notes.
      Participants will be excluded further from the study if at this point no intrauterine fluid
      collection is detected or if an intrauterine fluid collection containing a yolk sac or fetal
      pole is identified. Referral pathways to local Early Pregnancy Assessment Units (EPAU) will
      be in place for any woman in whom this early scan is strongly suggestive of an ectopic
      pregnancy, for example if there was an empty endometrial cavity and either an inhomogenous
      adnexal mass or an empty extra-uterine sac or a yolk sac or fetal pole with or without
      cardiac activity in an extra-uterine sac.

      All women will then have a routine viability ultrasound scan at between 6 and 7 weeks
      gestation as per the fertility unit's standard practice. This viability scan was performed by
      an appropriately trained doctor or nurse following standard operating procedures and using
      the same ultrasound equipment as the index test. This viability scan plus any subsequent
      clinical follow-up required i.e. if the diagnosis was not certain following the viability
      scan alone, will constituted the reference standard. Clinical follow-up will consist of a
      repeat transvaginal ultrasound (TVS) 7-10 days after the initial viability scan in cases of
      pregnancies of uncertain viability (defined as the presence of an intrauterine gestation sac
      of less than 25mm mean diameter with no obvious yolk sac or fetal pole or an intrauterine
      gestation sac containing a fetal pole of less than 7mm with no obvious fetal heart
      pulsations) and in cases of pregnancies of uncertain location (defined as no evidence of an
      intra- or extra-uterine pregnancy or retained products of conception on transvaginal
      ultrasound scan in the presence of a positive urinary pregnancy test), referral to a local
      EPAU for monitoring of serial serum human chorionic gonadotropin (β-hCG) levels and
      subsequent ultrasonography and possibly surgery where indicated according to departmental
      protocols until a definitive diagnosis can be made. Interpretation of the reference standard
      will be performed by an experienced gynaecologist without knowledge of the findings from the
      index test. Any uncertainty regarding the final diagnosis will be dealt with by seeking the
      opinion of two other senior gynaecologists and gaining a consensus opinion.

      The outcomes of interest are an intrauterine pregnancy (which may be viable or non-viable) or
      an ectopic pregnancy. A viable intrauterine pregnancy is defined as ultrasonographic
      identification of an intrauterine gestation sac with a fetal pole of any length with
      demonstrable fetal heart pulsations. A non-viable intrauterine pregnancy is defined as either
      an empty intrauterine gestation sac with mean sac diameter greater than 25mm or an
      intrauterine gestation sac containing a fetal pole with crown rump length greater than 7mm
      with no demonstrable fetal heart pulsations or in the absence of a viable embryo, no
      significant increase in the growth of the gestation sac or length of the fetal pole on two
      ultrasound scans performed more than 7 days apart. Where women undergo surgical or medical
      management of miscarriage, histological confirmation of the products of conception will be
      obtained when possible. Ectopic pregnancies will be confirmed either by direct visualisation
      during surgery with histological confirmation, or, in those managed medically with
      methotrexate or conservatively, unequivocal identification of an ectopic pregnancy on
      ultrasound scan. Ultrasonographic appearances indicative of an ectopic pregnancy will
      include: an empty endometrial cavity with either an inhomogenous adnexal mass or an empty
      extra-uterine sac or a yolk sac or fetal pole with or without cardiac activity in an
      extra-uterine sac. Following the reference standard, any pregnancy which does not fall into
      one of these categories will be excluded from the study. These included resolving or
      persisting pregnancies of unknown location.

      The sensitivity and specificity of the DDSS for predicting an intrauterine pregnancy (IUP)
      will be estimated following cross tabulation of the index test results against those of the
      reference standard. The overall diagnostic accuracy, as well as positive and negative
      likelihood ratios and predictive values, will also be calculated. Results will be expressed
      as percentages for ease of interpretation and 95% confidence intervals will also be given.
    

Intervention name(s): Transvaginal ultrasound scan
Intervention type(s): Procedure
Intervention description(s): The presence of the following structures will be recorded: an intrauterine fluid collection; the double decidual sac sign; yolk sac; and fetal pole.
Observational model: Cohort
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Participants will be recruited prospectively from Nurture Fertility, Nottingham, United
        Kingdom between 1st January and 31st October 2015. All women undergoing IVF/ICSI treatment
        will be invited to participate in the study.

        no ultrasonographic evidence of an intrauterine fluid collection, or a yolk sac and/or
        fetal pole was clearly visible within the intrauterine fluid collection. Women were also
        excluded if no outcome data were available or if, following the reference standard, the
        final diagnosis was not known (for example resolving or persistent pregnancies of unknown
        location).
      
Keywords: diagnostic accuracy; double decidual sac sign; intrauterine pregnancy