Methotrexate in an Intrauterine Pregnancy – An Interesting Twist

What was to blame for this fetal demise?

The patient in this case was a 36-year-old G3P2002, who presented to the emergency department (ED) on May 30 with complaints of lower abdominal pain (8 out of 10) and prior vaginal spotting. A urine pregnancy test was positive, with a subsequent quantitative human chorionic gonadotropin (hCG) level of 209 mIU/mL. Her vital signs were stable, with hemoglobin and hematocrit (H/H) levels of 12.7 g/dL and 35.9%, respectively.

An ultrasound revealed an endometrium that was 11 mm thick, with no visualized intrauterine gestational sac. There were no adnexal masses or fluid in the cul-de-sac. A right ovarian cyst measuring 1.5 cm was seen. The report noted no intrauterine gestational sac and the right ovarian cyst and gave a differential diagnosis of an early intrauterine pregnancy, ectopic pregnancy, or abortion. Correlation with hCG levels and a possible follow-up ultrasound were recommended.

The patient was seen in the same ED 5 days later, on June 4, with complaints of abdominal and right lower quadrant pain. She had an hCG level of 2,399 mIU/mL, with H/H levels of 12.6 g/dL and 36%. An ultrasound on this date revealed a small fluid collection within the endometrial cavity.

The radiologic interpretation noted the development of a fluid collection within the endometrium, which may represent an early gestational sac approximately 5 mm in diameter, too early to determine the fetal age. The right ovary had a 1.2-cm ovarian cyst. No adnexal masses were seen.

Three days later, on June 7, the patient was seen in the physician’s office. The note documented that the patient was seen in the ED for pain, with the last hCG level being 2,399 mIU/mL. The note also stated that a right ovarian cyst was seen, with no free fluid. An ultrasound in the physician’s office was interpreted as showing a double ring–like structure in the right adnexa less than 2 cm in diameter. The assessment was an ectopic pregnancy. The plan was to obtain an hCG level and administer methotrexate.

Methotrexate was administered prior to the return of the hCG level, which was 6484 mIU/mL. A repeat hCG level reading 4 days later was 13,232 mIU/mL. The patient was seen in the physician’s office 7 days later, on June 14, with an ultrasound interpreted as showing normal ovaries bilaterally and a right 3-cm adnexal cyst. On June 17, 3 days later, the patient was seen in the ED with an hCG level of 10,409 mIU/mL and H/H levels of 12.8 g/dL and 35.9%.

An abdominal ultrasound performed in the radiology department revealed an intrauterine pregnancy, with a crown rump length of 2.8 mm, with no cardiac activity identified. A resolving corpus luteum in the right ovary was noted. The patient was advised in the ED to follow up with her physician for obstetrical care and genetic counseling due to the previously administered methotrexate.

The patient was seen in the physician’s office on June 19, where a repeat ultrasound revealed a crown rump length of 4.7 mm, with no cardiac activity visualized. The diagnosis was a fetal demise, with a dropping hCG level. Subsequently, a dilation and curettage were performed.

The patient ultimately sued the physician for an incorrect diagnosis of an ectopic pregnancy and the negligent use of methotrexate in an intrauterine pregnancy.

At the trial, the plaintiff’s witnesses testified that the ultrasound on June 7, although of poor quality, was sufficient to identify an intrauterine gestational sac. In addition, the right ovarian “double ring” structure, interpreted to be an ectopic pregnancy, was actually the previously visualized right ovarian cyst, most likely a corpus luteum. Had the physician reviewed the prior studies, this would have been obvious.

Methotrexate was administered prior to the return of the hCG level, which increased appropriately to 6484 mIU/mL. The experts opined that this was a further breach of the standard of care.

Had the physician waited for the hCG level to return, methotrexate administration would have been delayed until the clinical situation was clearer. Thus, the correct diagnosis of an intrauterine pregnancy would have been made. In addition, there was no need to intervene on June 7, as the patient was clinically stable. The plaintiff’s experts further testified that the administration of methotrexate likely led to the early embryonic demise.

Learning Points

Juries often find for the physician
The use of methotrexate in an early intrauterine pregnancy is a current and ongoing concern. In this case, despite the weight of the evidence, the jury rendered a defense verdict, highlighting the fact that juries often find for physicians in malpractice cases. This was a fortunate outcome. However, the defense had to address several issues that made the case more difficult to defend.

Issues regarding hCG levels
In a stable patient, the physician is advised not to treat a suspected ectopic pregnancy with methotrexate based on a single hCG level, unless the ultrasound is definitive in the diagnosis. This patient had serial hCG levels that were rising appropriately. Although an appropriate increase in hCG level does not preclude the diagnosis of an ectopic pregnancy, it should cause the physician to reevaluate the diagnosis and treatment plan. For several reasons, the physician should know the hCG level results before administering methotrexate. An appropriate increase, as in this case, should prompt a reassessment of the patient. In addition, the hCG may be at such a level that, even in the case of a definite ectopic pregnancy, methotrexate may have a higher failure rate. Thus, surgical treatment may be more appropriate for the patient.

Issues regarding the ultrasound studies
Physicians should review prior imaging studies and compare the findings with current studies. Electronic health records, which often allow remote access to staff physicians, have facilitated this. A review of prior ultrasound findings, including the images if available, is helpful in constructing a timeline and arriving at the appropriate diagnosis.

Ultrasound quality
Ultrasounds were performed in the physician’s office with several different machines. The images were of relatively poor quality, likely related to the age of the ultrasound machines. Contemporary ultrasound machines should be used to acquire appropriate images. In addition, machines should undergo preventive maintenance on an annual basis to assure ongoing quality imaging.

Image retention
Images from the various studies were saved on thermal print paper, as is done frequently in offices. However, retaining images in a digital format is preferable, to maintain the quality of the originals. This can be done by using a picture archiving and communication system (PACS), in a local server, in the hospital’s PACS system, or in one of the various cloud-based PACS systems. Alternatively, one can migrate the images stored on an ultrasound machine’s hard drive to a DVD on a monthly basis and save the DVD in a secure location for the statute of limitations of one’s state.

Documentation
Office documentation was sparse and did not meet the then current guidelines for evaluation and management documentation. The history and physical findings should be adequately documented and correlated with laboratory and imaging findings. The assessment and plan should reflect one’s diagnostic assessment and treatment options. Finally, a discussion of the risks of the planned treatment and alternatives should be documented.

The defense experts stated that the patient had 2 ultrasounds, on May 30 and June 4, which did not confirm an intrauterine pregnancy. Further, on June 4, when the hCG level was more than 2000 mIU/mL (actual level, 2399 mIU/mL), an ultrasound should have revealed an intrauterine pregnancy if it was developing normally. Otherwise, a nonviable intrauterine pregnancy or ectopic pregnancy must be considered.

The defense further claimed that with the patient’s history of vaginal bleeding and continued abdominal pain, an ectopic pregnancy must be considered. The physician claimed that the ultrasound on June 7 was properly interpreted, with no visualized intrauterine gestational sac and a double ring–like structure in the right adnexa, consistent with an ectopic pregnancy. As such, the administration of methotrexate was appropriate.

After 4 hours of deliberation, the jury returned a defense verdict.

The ultrasound images and interpretation did not meet applicable guidelines. Guidelines from the American Institute of Ultrasound in Medicine for appropriate imaging for both obstetrics and gynecology are available here. Documentation guidelines are also available here. If one adheres to such guidelines, a case is more defensible.

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