Endometriosis affects an estimated ten percent of women of reproductive age worldwide and occurs when tissue resembling the uterine lining grows outside the uterus. For decades, clinicians have recognized that the disease is not uniform. Superficial endometriosis involves implants resting on the peritoneum, the membrane lining the pelvis, whereas deep infiltrating endometriosis describes lesions that invade at least five millimeters beneath the surface, often embedding into the rectovaginal septum, bowel, bladder, or uterosacral ligaments. These lesion types differ in anatomy, hormonal behavior, pain burden, and fertility impact. Yet most studies of pregnancy outcomes have lumped all forms together, leaving open whether the more aggressive phenotype genuinely worsens perinatal prognosis or whether previously reported risks reflect confounding by infertility treatments and surgical history.

The Istanbul team addressed that gap by restricting their analysis to women whose diagnoses were surgically confirmed, eliminating the imaging-based ambiguity that clouds many registry studies. They compared 102 pregnancies in women with deep infiltrating disease against 166 pregnancies in women with superficial disease, all delivered at a single tertiary referral center. The primary endpoints were deliberately practical: placenta previa, the condition in which the placenta covers the cervical opening, and preterm birth before 37 completed weeks of gestation. Secondary outcomes spanned a broader basket of placental complications, maternal perinatal events, and measures of newborn morbidity, including admission to the neonatal intensive care unit.

Because the two patient groups differed in ways that could independently influence pregnancy, the researchers employed multivariable logistic regression, a statistical technique that estimates the effect of one factor while holding others constant. Their models adjusted for maternal age, pre-pregnancy body mass index, parity, the use of assisted reproductive technology, the presence of adenomyosis, and previous uterine surgery. This matters because women with deep disease are more likely to undergo major pelvic operations and fertility procedures, both of which have been linked in earlier literature to abnormal placentation. Without such adjustment, any apparent association between lesion depth and placental pathology could simply have been a proxy for treatment history.

The adjusted results were striking. Placenta previa occurred significantly more often in the deep infiltrating group and remained independently associated with the condition after correction, yielding an adjusted odds ratio of 2.41 with a 95 percent confidence interval spanning 1.02 to 5.68. In clinical terms, women with DIE had roughly two and a half times the odds of this dangerous placental location compared with women whose disease was superficial. Preterm birth also trended upward in the deep disease group, but that association lost statistical significance once confounders were removed, suggesting the raw difference owed something to the population characteristics rather than the lesion biology alone.

Perhaps the most consequential finding concerned the composite placenta-related outcome, which combined placenta previa and placental abruption, the premature detachment of the placenta from the uterine wall. Even after full statistical adjustment, this composite remained independently associated with deep infiltrating endometriosis. The pattern points toward disordered placentation as the central mechanism linking deep pelvic disease to obstetric harm. Researchers have proposed several pathways: chronic inflammation within the pelvis may alter uterine receptivity and vascular remodeling, prior excision of bowel or vaginal lesions can disturb the lower uterine segment and cervix, and molecular changes in endometrial tissue may impair the normal invasion of trophoblast cells that anchor and feed the placenta.

Neonatal outcomes reinforced the picture. Admission to the neonatal intensive care unit was more frequent among babies born to mothers with DIE, and the association survived adjustment with an odds ratio of 1.89 and a confidence interval of 1.01 to 3.54. A confidence interval that begins just above one signals a robust but borderline result; it means the true effect could plausibly range from a near-negligible increase to nearly a fourfold rise in NICU admission risk. Because the analysis was confined to singleton pregnancies, the neonatal signal cannot be explained by the prematurity and low birth weight that commonly accompany twin gestations conceived through assisted reproduction.

The study carries the honest limitations typical of its design. As a single-center retrospective cohort drawing on medical records rather than prospective data collection, it inherits the risk of misclassification and of undetected confounders, such as smoking, medication exposure, or the precise surgical extent of lesion excision. The sample size of 268 pregnancies, while respectable for a surgically confirmed cohort of deep disease, limits statistical power for rarer outcomes like abruption, which is why the investigators bundled it into a composite endpoint. Reverse causation also cannot be excluded: the same severity of disease that drives women to major surgery may itself reflect a more biologically aggressive process that independently affects placentation. The authors accordingly frame their results as hypothesis-generating rather than definitive, calling for lesion-based phenotyping in larger, multicenter, prospective cohorts.

Nevertheless, the clinical implications are immediate and actionable. Endometriosis already affects as many as one in ten women, and the deep infiltrating subtype, historically underdiagnosed because of its insidious symptoms and the expertise required to identify it laparoscopically, is being recognized with increasing frequency at specialized centers. If lesion depth can be confirmed before conception, whether through surgical notes, magnetic resonance imaging, or transvaginal ultrasound mapping, obstetric teams could stratify patients early, schedule growth scans and placental localization studies with greater vigilance, and deliver in centers equipped for hemorrhage management and advanced neonatal care. Placenta previa in particular demands anticipation, since it complicates delivery planning and carries substantial risk of massive postpartum bleeding.

The broader scientific message may prove even more important than the odds ratios. Endometriosis is a disease of phenotypes, and the Istanbul data add pregnancy physiology to the growing list of outcomes, from pain and infertility to ovarian cancer risk, in which lesion biology matters more than diagnosis labels. A woman with superficial implants may be reassured that her obstetric risk profile resembles that of the general population far more closely than the averages reported in older studies that merged all disease forms. A woman with deep disease, by contrast, deserves a conversation about placental monitoring during her first prenatal visit. As surgical mapping and noninvasive phenotyping improve, the researchers argue that lesion-specific risk stratification could transform endometriosis from a static diagnosis into a dynamic perinatal risk model, one that follows each patient from her first pelvic scan to her delivery room.

Subject of Research: Obstetric and neonatal outcomes in pregnancies complicated by deep infiltrating versus superficial endometriosis

Article Title: Obstetric and Neonatal Outcomes in Deep Infiltrating Versus Superficial Endometriosis: A Retrospective Cohort Study

Article References: Baglar, İ., Topaloglu, T., Keles, E., Yılmaz, A., Kopuk, S. Y., Civi, B. Y., Guliyeva, K. A., Nokay, E., Karahan, M., & Agir, D. (2026). Obstetric and Neonatal Outcomes in Deep Infiltrating Versus Superficial Endometriosis: A Retrospective Cohort Study. Reproductive Sciences. https://doi.org/10.1007/s43032-026-02215-3

Image Credits: AI Generated

DOI: 10.1007/s43032-026-02215-3

Keywords: deep infiltrating endometriosis, superficial endometriosis, placenta previa, preterm birth, pregnancy outcomes, neonatal intensive care, placental abruption, retrospective cohort study, obstetrics, reproductive medicine, endometriosis phenotyping, adjusted odds ratio

FAP is a membrane protein expressed by activated fibroblasts, the stromal cells that remodel tissue in fibrotic and inflammatory environments. In oncology, FAP has become one of the most successful molecular imaging targets of the past decade, because fibroblast activation protein is largely absent from normal adult tissues but abundant in the cancer-associated stroma of many epithelial tumors. Radiolabeled FAP inhibitors, commonly referred to as FAPI tracers, allow positron emission tomography to light up tumors with striking contrast. More recently, clinicians have reported incidental FAPI uptake in endometriosis lesions and even suggested that FAP-targeted PET could offer diagnostic value beyond MRI in selected patients. What remained unclear, however, was the biological foundation for those observations: how strongly do endometriotic lesions actually express FAP, and does the level of expression depend on whether a lesion is visible on the imaging tests women typically receive?

The Mayo Clinic team, led by corresponding author Hiroaki Takahashi, set out to answer precisely that question. Because no one had previously linked FAP expression in endometriosis to lesion-by-lesion visibility on MRI and transvaginal ultrasound, the investigators designed a retrospective study that combined pathology, immunohistochemistry, and blinded imaging review. They analyzed surgical specimens from patients with histologically confirmed deep endometriosis and superficial endometriosis, all of whom had undergone MRI, transvaginal ultrasound, or both before surgery. The final cohort included thirteen patients with deep endometriosis and nine with superficial disease, providing a matched basis for comparing the two phenotypes at the tissue level.

To quantify FAP expression, the researchers used immunohistochemical staining of the resected specimens and calculated H-scores, a standard pathology metric that incorporates both the intensity of staining and the proportion of positive cells. H-scores range from zero to 300, allowing semi-quantitative comparison across samples. As a benchmark, the team also stained colorectal adenocarcinoma controls, since colorectal cancer is known to be a FAP-expressing malignancy and therefore provides a reference point for interpreting stromal signal intensity. The comparison showed that endometriosis, across both deep and superficial forms, exhibited substantial FAP expression in its fibroinflammatory stroma, although the H-scores were significantly lower than those of the colorectal cancer controls.

A key finding was that FAP expression did not differ significantly between deep and superficial endometriosis. Median H-scores were 170 for deep lesions and 200 for superficial lesions, a difference that was statistically indistinguishable. This is a notable result because superficial endometriosis is precisely the subtype that most often escapes detection on standard imaging. If superficial implants carry FAP expression comparable to deep lesions, then a whole-body molecular imaging technique targeting FAP should, in principle, be able to detect superficial disease that MRI and ultrasound routinely miss. The study thereby provides a histopathological rationale for extending FAP-targeted PET imaging from oncology into benign inflammatory and fibrotic gynecological disease.

The second half of the study addressed the visibility question directly. Two abdominal radiologists independently reviewed the MRI and transvaginal ultrasound studies and graded the visibility of each pathology-confirmed lesion on a study-specific scale from zero to three, with scores of zero and one classified as low visibility and scores of two and three as high visibility. When a lesion’s location fell outside the available field of view, it was assigned a designation of not applicable and excluded from the visibility comparison. This blinded, reader-based design ensured that the imaging assessments were independent of the pathological FAP results, allowing an unbiased test of whether molecular expression tracks with detectability.

For MRI, no lesions were graded as outside the field of view by either reader, and the low- versus high-visibility split was uneven but workable: Reader 1 classified 5 lesions as low visibility and 16 as high visibility, while Reader 2 classified 3 as low and 18 as high. Median H-scores for the low- and high-visibility groups were 220 and 170 for both readers. Although the low-visibility lesions trended toward higher FAP expression, the differences were not statistically significant. In practical terms, MRI-visible and MRI-invisible endometriosis lesions expressed FAP at broadly similar levels, suggesting that poor visibility on MRI reflects the limitations of anatomical imaging rather than any fundamental difference in the biology of the lesion.

The transvaginal ultrasound results told a more complicated story. Because ultrasound has a limited field of view in the pelvis, one lesion for Reader 1 and two lesions for Reader 2 fell outside the imaging field and were designated not applicable. Among the evaluable lesions, the low-visibility groups were small, containing just two lesions for Reader 1 and one for Reader 2, compared with ten high-visibility lesions for each reader. Median H-scores in the low-visibility groups were 48 and 20, markedly lower than the 165 and 160 observed in the high-visibility groups. The authors are careful to note that these small sample sizes preclude firm conclusions. The apparent association between low ultrasound visibility and lower FAP expression may reflect the small number of evaluable lesions rather than a genuine biological pattern, and larger studies will be needed to determine whether FAP expression correlates with sonographic detectability.

Even with those caveats, the overall conclusion of the study is clear and clinically important: both deep and superficial endometriosis show substantial stromal FAP expression, and critically, superficial lesions that are poorly seen on conventional imaging still express the target. The findings arrive amid a growing literature on FAPI PET beyond cancer. FAP-targeted imaging has been explored in Crohn’s disease, rheumatoid arthritis, and other fibroinflammatory conditions, and several recent case reports and small series have documented FAPI uptake in endometriotic implants, including focal uptake at the rectouterine pouch and subtype-specific uptake patterns that added diagnostic information beyond MRI. Earlier laboratory work had already shown that FAP-positive activated fibroblasts are detectable in the endometriotic microenvironment, where they correlate with stroma composition and with infiltrating CD8-positive and CD68-positive immune cells. The new Mayo Clinic study adds the missing translational link between that biology and the day-to-day imaging visibility of the disease.

The implications extend to diagnosis, surgical planning, and potentially therapy. Delayed diagnosis of endometriosis remains a global problem, with patients commonly waiting years from symptom onset to confirmation, partly because superficial implants are difficult to detect with anatomical imaging and often require laparoscopy for diagnosis. A molecular imaging approach that targets the fibroinflammatory stroma shared by deep and superficial lesions could complement MRI and ultrasound, particularly in mapping disease extent before surgery and in identifying active, fibrotically active lesions among otherwise inconspicuous findings. FAP is also being investigated as a therapeutic target, so confirming its expression in endometriotic tissue opens a second avenue beyond diagnosis. The authors note that their study is retrospective and modest in size, with only twenty-two patients, and that the ultrasound visibility analysis was limited by small numbers. Prospective studies with larger cohorts will be needed to establish how FAPI PET performs against MRI and transvaginal ultrasound in head-to-head diagnostic comparisons. Nevertheless, by demonstrating that even imaging-invisible superficial endometriosis carries the molecular signature that FAP-targeted tracers exploit, the study lays the histopathological groundwork for what could become the first molecular imaging strategy purpose-built for the full phenotypic spectrum of endometriosis.

Subject of Research: Fibroblast activation protein expression in deep and superficial endometriosis and its relationship to MRI and transvaginal ultrasound visibility

Article Title: FAP expression in deep and superficial endometriosis: Association with MRI and transvaginal ultrasound visibility

Article References: FAP expression in deep and superficial endometriosis: Association with MRI and transvaginal ultrasound visibility. (n.d.). https://doi.org/10.1007/s00259-026-08189-3

Image Credits: AI Generated

DOI: 10.1007/s00259-026-08189-3

Keywords: endometriosis, fibroblast activation protein, FAPI PET, molecular imaging, deep endometriosis, superficial endometriosis, MRI, transvaginal ultrasound, immunohistochemistry, H-score, radiology, diagnostic imaging