Extrauterine pregnancy, or extrauterine pregnancy (EUG for short), is a complication of first trimester pregnancy. In this case, the already fertilized egg has not reached the uterine cavity and has settled outside the uterus. Accordingly, even an ultrasound scan may miss the fertilized egg. In most EUG, the fertilized zygote nests in the fallopian tubes, in which case one can speak of an ectopic pregnancy. According to current medical knowledge, embryos from an EUG (except for an ectopic pregnancy) are usually not viable due to inadequate nutrient supply. Additionally, all EUGs pose a risk to the mother, as life-threatening bleeding (e.g., due to rupture of the fallopian tube) can occur. The likelihood of EUG increases as the pregnant woman ages.
Generally, the detection of the pregnancy hormone hCG (i.e., human chorionic gonadotropin) in the urine sample or blood serum is considered to establish pregnancy. This is followed, in most cases, by an ultrasound scan to detect the embryo in the uterus. If the fertilised cell cannot be detected, this is initially referred to as pregnyncy of unknown location, or PUL for short. This can also indicate an EUG, especially if the hormone hCG can still be detected, but its concentration does not increase in contrast to a normal pregnancy. This is also called persistent PUL. Other possible approaches are controversial.
A regular procedure is called a curettage or abrasion. This involves removing all, or part, of the lining of the uterus. Detection of chorionic villi (i.e. protrusions of the outer amniotic cavity) can prove pregnancy loss and thereby also rule out EUG.
If after the curettage the levels of pregnancy hormones still do not drop, an additional method of treatment with methotrexate can be used. There is still the possibility that the active substance is used without a curettage. In this case, a second dose is administered after four days. In the third option, further development is first waited for and observed by hormone controls, because there is also the possibility that a uterine pregnancy has been overlooked. In this case, the hCG levels would rise again on their own.
It is this decision of which treatment method is now the best strategy that the so-called "ACT or NOT" study investigated. The researchers wanted to determine if active treatments with methotrexate were more effective than a strategy for expecting pregnancy.
For this purpose, the randomized, multicenter clinical trial, published in 2021 in the journal JAMA, studied 255 women with stable blood flow and a diagnosed persistent PUL pregnancy with an unlocated embryo. Between July 2014 and June 2019, subjects with a median age of 31 years were recruited from 12 medical centers in the United States.
Subjects were randomized in a 1:1:1 ratio to include either active treatment with curettage and methotrexate if needed (n = 87), active treatment with methotrexate in two doses (n = 82), or treatment waiting.
The primary end goal was successful pregnancy resolution without a change in the actual treatment strategy. First, we examined whether the active treatment groups recorded better scores than the wait-and-see strategy. Next, we examined whether dual administration of methotrexate was inferior to active treatment after curettage.
Those selected for wait-and-see treatment were significantly less likely to experience successful termination of pregnancy without needing further treatment compared to women who underwent an active treatment regimen. Among active treatments, pregnancy termination occurred in 94.5% of cases. A treatment method was considered to have failed if it resulted in an EUG that required further surgical or drug therapies. In a wait-and-see approach, this was the case in 56.1%. The wait-and-see group also had a higher incidence of surgical intervention (21.5% vs. 5.5% with active treatment), curettage (15% vs. 5.5%), or laparoscopic surgery (9.3% vs. 4.1%).
Dual methotrexate use was non-inferior to drug administration after curettage in terms of successful termination of pregnancy.
For all treatment strategies, the most common adverse event was vaginal bleeding in 44.2-52.9% of subjects.
In summary, pregnancy was more likely to be successfully resolved in patients with persistent PUL using active treatment methods compared to a wait-and-see strategy, without the need for additional forms of therapy. Despite these study results, individualized selection of a treatment strategy discussed with a physician or health care professional is significant. After all, 27% rejected a wait-and-see strategy, 48% a curettage and 42% of the subjects were against a double treatment with methotrexate. In one pregnant woman in the wait-and-see treatment group, the hCG level returned to normal after some time and she experienced a complication-free pregnancy with a healthy child - a scraping or drug administration would probably dissolve embryonic development.