Shabnam Bobdiwala1 and Tom Bourne1
Queen Charlotte and Chelsea Hospital, Imperial College London, Du Cane Rd., W12 0HS London, UK
Shabnam Bobdiwala (Corresponding author)
Pregnancy of unknown locationMethotrexateDiscriminatory zone
A 28-year-old woman was referred to the emergency department by her family practitioner after presenting with a 4-day history of left iliac fossa discomfort. The urinary pregnancy test was positive. She stated that her last menstrual period (LMP) was 6 weeks ago. She had a past history of chlamydia infection. Transvaginal ultrasonography revealed a hypoechoic area within the uterine cavity measuring 4.3 mm in maximum diameter. This was interpreted as a pseudosac (Fig. 3.1). The patient was tender in the left iliac fossa during the scan, and the left ovary was not clearly visualized. On presentation, the serum hCG was 1600 mIU/mL, and 48 h later had increased to 2200 mIU. The patient’s pain settled over this time period. It was felt that these findings were consistent with an ectopic pregnancy (EP) and methotrexate was given.
An early intrauterine gestation sac misclassified as a pseudosac
Diagnosis and Assessment
A patient presenting with risk factors for EP (e.g. previous pelvic infection) should heighten suspicion. The greatest risk factor for an EP is tubal damage, which usually occurs after tubal surgery or following a pelvic infection, particularly with Chlamydia trachomatis. Others include smoking and conception following assisted reproduction. However, it must be remembered that most EPs occur in women who do not have any risk factors . Dating a pregnancy by LMP is helpful but not necessarily an accurate predictor of what to expect to see on an ultrasound scan . A significant proportion of women are unsure of their dates or have irregular cycles. Furthermore, we know there are clinically relevant variations in the ovulation–implantation interval .
Transvaginal ultrasonography is the best imaging modality for investigating problems in early pregnancy, with > 70 % of EPs visualized at presentation and > 90 % before surgery using this approach . The majority (60 %) of EPs will be identified as a small homogeneous mass (blob sign, Fig. 3.2) rather than the classically described ring or ‘bagel’ sign . The concept of a ‘pseudosac’ is to some extent outdated and relates to a misinterpretation of the ultrasound findings. A round or oval fluid-filled hypoechogenic collection in the uterus in a woman with a positive pregnancy test is more likely to be an early intrauterine gestation sac and should not be cited as evidence for the presence of an EP . Great care should also be taken when performing a scan in women when the uterus is axial or in the presence of fibroids. Both can make it difficult to identify an early intrauterine gestation sac.
A homogeneous mass or ‘blob sign’—the commonest ultrasound feature of an ectopic pregnancy
The case presented had a pregnancy of unknown location (PUL) , not a confirmed EP. The correct management would have been to repeat the transvaginal ultrasound scan at an interval to see if the hypoechogenic area in the endometrial cavity could be definitively identified as an intrauterine pregnancy, or an EP mass visualized before considering methotrexate.
The modern management of PUL is based on assigning risk (low risk: failing PUL and viable intrauterine; high risk: EP) rather than locating the pregnancy. Such risk assessment may be carried using the hCG ratio (hCG at 48 h/hCG at 0 h), although we have recently shown the mathematical prediction model ‘M4’ based on the initial hCG and hCG ratio is effective in this context and outperforms single measurements of progesterone and the hCG ratio alone . This model can be downloaded from: http://homes.esat.kuleuven.be/~biomed/M4PUL/M4triage.htm.
When considering methotrexate administration, it is important to exclude a viable intrauterine pregnancy. Methotrexate can be safely given when an EP has been definitively visualized. However, as most EPs are seen as a homogenous mass , false positive test results are possible. Accordingly, waiting 48 hours and reviewing the hCG ratio prior to methotrexate administration can significantly reduce the risk of inadvertent termination. A serum hCG rise of < 35 % is highly unlikely to be associated with a viable intrauterine pregnancy . In this case, the rise in serum hCG of 37.5 % should have alerted the clinical team that the presence of a viable intrauterine pregnancy is potentially possible. A further safeguard prior to methotrexate administration is to ensure a clinician who has specific expertise in early pregnancy imaging has repeated the ultrasound scan.
Historically, it was felt that a viable pregnancy would result in a doubling of serum hCG levels , a failing pregnancy, a halving of serum hCG levels and an EP, a ‘suboptimal rise’ in serum hCG after 48 hours. This does not, however, necessarily aid the clinician in determining the location of the pregnancy as EPs may demonstrate a ‘doubling’ or ‘halving’ of the serum hCG. In contrast, 8 % of viable intrauterine pregnancies have been found to demonstrate a ‘suboptimal rise’ in hCG levels, as seen in this case . In any event, management is based on risk assessment. If the serum hCG is falling, the pregnancy will fall into the low-risk category irrespective of whether it is in the uterine cavity.
In a woman with a PUL and a serum hCG of > 2000 mIU/mL, the most likely diagnosis is not an EP but a non-viable intrauterine pregnancy. Similarly, a viable intrauterine cannot be entirely excluded when the serum hCG is > 2000 mIU/mL . Accordingly, methotrexate should not be given solely on the basis of there being a PUL with an initial hCG above this level . In the event of a stable visualized EP, it is sensible to delay decisions about treatment until a second serum hCG result is available 48 hours later. Information given by the hCG ratio will allow the clinician to know if a viable intrauterine pregnancy is a possibility. In the event that the hCG level is falling, expectant management may also be an option, thus avoiding medical intervention altogether. Giving methotrexate as a first line treatment without taking these precautions may be hazardous.
The consequences of missing the diagnosis of a wanted intrauterine pregnancy are potentially far greater than delaying the diagnosis of an EP in a haemodynamically stable patient. The absolute serum hCG level does not predict the likelihood of rupture , and most patients who are haemodynamically stable can be safely managed either expectantly or medically.
In relation to uterine curettage, current evidence suggests that there is a limited role for uterine curettage as a diagnostic tool in women who are classified as having a PUL . The concern is that there may be inadvertent termination of wanted pregnancies. It is important to be aware that the rise in hCG that is incompatible with a possible intrauterine pregnancy may be as low as ≤ 15 % over 48 h . This is a different context to using uterine curettage in the small cohort of women classified as having a ‘persistent PUL’, where serum hCG levels persistently fail to decline (over ≥ 3 serial serum hCG measurements). Using uterine curettage in this circumstance to confirm the absence of chorionic villi within the uterine cavity before giving methotrexate is reasonable. However, false negatives can occur; for example, chorionic villi are not detected by histopathology in 20 % of curettage specimens from elective termination of pregnancy.
The patient received a single dose of intramuscular methotrexate (50 mg/m2 body surface). Subsequent ultrasonography 14 days later demonstrated an intrauterine gestation sac with a yolk sac. Both ovaries were seen and appeared normal with no adnexal masses. The pregnancy was followed up for the next 4 weeks and ultimately miscarried. The patient took legal action against the gynaecologist and the hospital.
· Most EPs are in women who have no risk factors.
· Dating a pregnancy by the last menstrual period is not an accurate predictor of ultrasound findings.
· A round or oval fluid-filled collection in the uterus is more likely to be an early intrauterine gestation sac than a pseudosac.
· A suboptimal rise in the serum hCG level is not diagnostic of an EP.
· A serum hCG level of > 2000 mIU/mL should not be used as an indication of the presence of an EP. It is more likely to represent an intrauterine pregnancy and does not exclude viability.
· Most EPs (> 70 % on initial presentation and > 90 % before final treatment) should be visualized on transvaginal ultrasonography. Most EPs (60 %) are seen as homogenous masses or ‘blobs’.
· The management of PUL is based on assigning risk and not necessarily locating the pregnancy.
· In the event of a stable EP, it is sensible to repeat the hCG after 48 hours before considering treatment.
· If the hCG ratio does not exclude a viable intrauterine pregnancy, a repeat ultrasound scan may be carried out to ensure there is certainty about the diagnosis.
· If the hCG is declining, expectant management may be chosen, avoiding the need for methotrexate.
· The serum hCG level does not predict the likelihood of rupture of an EP.
· There is a limited role for uterine curettage as a diagnostic tool in women with a PUL.
· Uterine curettage is reasonable prior to management with methotrexate in patients classified with a ‘persistent PUL’.
Tom Bourne is supported by the NIHR Biomedical Research Center based at Imperial College Healthcare NHS Trust and Imperial College London. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health.
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