Is endometriosis typology a potentially better classification system for assessing risk of female infertility?

Definition of Infertility and Indications for Fertility Evaluation: Consensus Document

Minjeur M et al., 2026 · Journal of Restorative Reproductive Medicine · Free to read

Infertility is a clinical condition that is recognized by the symptom of an inability to conceive through sexual intercourse or to sustain a pregnancy, with that symptom indicating underlying male and/or female pathology. This definition of infertility was developed through a structured, consensus-informed process involving broad stakeholder engagement. Initially, multiple definitions currently used by various medical professional organizations were reviewed, and a definition document was drafted and submitted to the Board of Directors of the International Institute for Restorative Reproductive Medicine (IIRRM). All IIRRM members were invited to provide feedback on the draft. Approximately 2,500 individuals and 44 organizations from 92 countries were then invited to review the proposed document, representing clinical, scientific, patient, policy, and advocacy perspectives. Submitted comments were reviewed thematically, with suggested revisions evaluated for clarity, clinical relevance, inclusiveness, and consistency with contemporary restorative reproductive medicine. Following this review, 3 substantive changes, 18 minor changes, and 15 citation corrections were incorporated into the final draft which resulted in a revised definition intended to better reflect the medical, social, and practical realities of modern infertility evaluation and care. Final approval by the IIRRM Board of Directors was unanimous.

Subfecundity, Infertility Treatment, and Child Neurodevelopment

Kahn LG et al., 2026 · JAMA Network Open · Free full text on PubMed Central

Increasing numbers of children are conceived using infertility treatment; concerns remain about potential effects on child neurodevelopment. To evaluate whether infertility treatment is associated with child neurodevelopment and whether such an association may be attributable to underlying subfecundity. DESIGN, SETTING, This cohort study was conducted among mother-child dyads in the National Institutes of Health Environmental Influences on Child Health Outcomes (ECHO) Cohort, with infants conceived between 1998 and 2022. Associations of subfecundity and infertility treatment with neurodevelopmental outcomes were assessed among children ages 2 to 10 years. Data were analyzed from May 14, 2025, to March 31, 2026. Subfecundity was defined as prior consultation for, treatment of, or diagnosis of infertility for either partner; at least 2 prior miscarriages; or ever having had unprotected heterosexual intercourse for 12 months without conceiving. Infertility treatment was categorized as in vitro fertilization (IVF) or non-IVF treatment. Harmonized caregiver responses to the Strengths and Difficulties Questionnaire and the Child Behavior Checklist yielded continuous raw scores for externalizing and internalizing problems. The total raw Social Responsiveness Scale (SRS) score quantified autism-like symptoms. Caregivers reported physician diagnosis of autism spectrum disorder (ASD) and attention deficit/hyperactivity disorder (ADHD). Among 15 382 mother-infant dyads, there were 14 191 unique maternal participants (mean [SD] age at delivery, 30.9 [5.33] years; 8780 parous participants [57.1%]). ASD and ADHD were diagnosed in 876 offspring (7.6%) and 819 offspring (7.1%), respectively. In generalized linear models, subfecundity was associated with higher externalizing problem and SRS scores among all pregnancies (externalizing problems: b = 0.47 [95% CI, 0.14-0.81]; SRS score: b = 1.08 [95% CI, 0.01-2.14]) and when restricted to natural conceptions (externalizing problems: b = 0.45 [95% CI, 0.07-0.83]; SRS score: b = 1.12 [95% CI, -0.09 to 2.34]). Offspring of parents with subfecundity had higher odds of ASD (overall: odds ratio [OR], 1.27 [95% CI, 1.03-1.57]; natural conceptions: OR, 1.31 [95% CI, 1.04-1.64]). Children conceived via non-IVF treatment had higher odds of ADHD compared with those conceived via natural conception with subfecundity (OR, 1.77 [95% CI, 1.16-2.68]) or without subfecundity (OR, 1.54 [95% CI, 1.05-2.25]). There were no significant associations for IVF treatment. In this large US cohort study, subfecundity was associated with elevated scores for caregiver-reported symptoms of behavioral problems and higher odds of ASD diagnosis, independent of infertility treatment. Non-IVF treatment was associated with ADHD, warranting further research into specific indications for treatment that may increase risk of offspring neurodevelopmental problems.

Potential increase of the U.S. total fertility rate resulting from restorative treatment of unresolved subfertility: a simulation study

Stanford JB et al., 2026 · Frontiers in Reproductive Health · Free full text on PubMed Central

Background The total fertility rate (TFR) in most developed countries has been declining for decades. In the United States (U.S.), the total fertility rate has remained below replacement level since 2007. Subfertility affects at least 15% of women or couples over their reproductive lifespan and contributes to reduced TFR. Restorative reproductive medicine (RRM) is a medically based approach to subfertility care that can be delivered in primary care settings to increase live birth rates. Objective To estimate the theoretical impact of use of RRM among subfertile couples in the United States. Methods We conducted a simulation study. Model inputs included the number of women of reproductive age in the United States by 5-year age groups; current age-specific and total fertility rates; the proportion of women in each age group with subfertility; estimated spontaneous live birth rates among women with subfertility; and age-specific crude live birth rates with RRM treatment. We evaluated fifteen scenarios including sensitivity analyses: two different varying assumptions for spontaneous conception (25% vs. 50%), two levels of RRM utilization among subfertile women (20% vs. 50%), three different estimates of the number of subfertile women who would be potentially eligible for RRM treatment, and 4 different levels of effectiveness (live birth) from RRM treatment. Results The baseline TFR in the United States was 1.77 during 2015-2019, and 13.5% of women ages 20-44 were estimated to have subfertility. In a conservative scenario (50% spontaneous births; 20% RRM utilization; married women trying to conceive for at least 12 months, 20.7% RRM live births), the TFR increased to 1.79, representing a 1.0% relative increase (absolute +0.02). In an optimistic scenario (25% spontaneous births; 50% RRM utilization; all subfertile women), the TFR increased to 2.02, a 14.5% relative increase (absolute +0.26), approaching replacement-level fertility. Conclusion Simulation results suggest that expanding access to RRM within primary care settings could meaningfully increase the U.S. TFR, by reducing unresolved subfertility. Realizing this potential would require policy and health system changes to address workforce capacity, insurance coverage, and equitable access. These findings underscore the potential contribution of non-IVF fertility care pathways in addressing population-level fertility decline.

Restorative Reproductive Medicine Restricting Access to Care

Minjeur M et al., 2026 · JAMA

Endometriosis diagnosis, staging and typology and adverse pregnancy outcome history

Schliep KC et al., 2022 · Paediatr Perinat Epidemiol · Free full text on PubMed Central

Women with endometriosis may have an increased risk of adverse pregnancy outcomes. Research has focused on infertility clinic populations limiting generalisability. Few studies report differences by endometriosis severity. We investigated the relationships between endometriosis diagnosis, staging and typology and pregnancy outcomes among an operative and population-based sample of women. Menstruating women ages 18-44 years enrolled in the ENDO Study (2007-2009), including the operative cohort: 316 gravid women undergoing laparoscopy/laparotomy at surgical centres in Utah and California; and the population cohort: 76 gravid women from the surgical centres' geographic catchment areas. Pregnancy outcomes were ascertained by questionnaire and included all pregnancies prior to study enrolment. Endometriosis was diagnosed via surgical visualisation in the operative cohort and pelvic magnetic resonance imaging in the population cohort. Adjusted prevalence ratios (aPR) and 95% confidence intervals (CI) were estimated using generalised linear mixed models for pregnancy outcomes, adjusting for women's age at study enrolment and at pregnancy, surgical site, body mass index and lifestyle factors. Women in the operative cohort with visualised endometriosis (n = 109, 34%) had a lower prevalence of live births, aPR 0.94 (95% CI 0.85, 1.03) and a higher prevalence of miscarriages, aPR 1.48 (95% CI 1.23, 1.77) compared with women without endometriosis. The direction and magnitude of estimates were similar in the population cohort. Women with deep endometriosis were 2.98-fold more likely (95% CI 1.12, 7.95) to report a miscarriage compared with women without endometriosis after adjusting for women's age at study enrolment and at pregnancy, surgical site and body mass index. No differences were seen between endometriosis staging and pregnancy outcomes. While there was no difference in number of pregnancies among women with and without endometriosis in a population-based sample, pregnancy loss was more common among women with endometriosis, notably among those with deep endometriosis.

Abstract P1174: Endometriosis diagnosis, staging, and typology in relation to inflammatory cytokines

Shaaban M et al., 2025 · Circulation

Endometriosis, affecting 11% of reproductive-aged persons, is characterized by ectopic endometrial tissue and chronic inflammation. Prior research suggests those with endometriosis have higher cardiovascular disease risk, but mechanisms remain elusive. The objective of this study is to assess whether endometriosis diagnosis, staging, and typology (superficial endometriosis (SE), ovarian endometriomas (OE), and deep infiltrating endometriosis (DE)) are associated with serum interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor alpha (TNF-) concentrations. The study analyzed data from 395 premenopausal persons in Utah undergoing gynecologic laparoscopy who participated in the NICHD ENDO study (2007–2009). Post-operative reports determined endometriosis typology (SE, OE, DE) and staging (minimal, mild, moderate, severe) using Revised American Society for Reproductive Medicine classification. Elevated serum cytokine concentrations were defined as IL-6 ≥2pg/mL, IL-8 ≥3pg/mL, and TNF- ≥7.5pg/mL. Generalized linear models generated adjusted prevalence ratios (aPR) 95% CI controlling for age, BMI, marital status, race/ethnicity, and serum cotinine. Participants were on average 32 years (SD=7) at time of gynecologic laparoscopy/laparotomy, non-Hispanic white (79%), married (71%), mean BMI 28 (SD=8) and non-smokers (83% serum cotinine <10ng/mL). Forty-two percent (n=166) were diagnosed with incident endometriosis. We found no differences among those with, compared to without, endometriosis and elevated IL-6, 12% vs 10%, aPR: 1.01 (0.97, 1.10), IL-8, 5% vs 8%, aPR: 0.99 (0.94, 1.04); and TNF, 16% vs 13%, aPR: 1.00 (0.96, 1.04). While there were no statistically significant associations between endometriosis staging or typology and cytokines, those with moderate to severe endometriosis had nonsignificant lower IL-6 and IL-8 (aPR: 0.61 [0.15, 2.52] and aPR: 0.74 [0.17, 3.20]) but higher TNF- (aPR: 1.27 [0.56, 2.84]), compared to no endometriosis. Individuals with OE and DE had nonsignificant trends of IL-6 and Il-8 (aPR: 0.86 [0.11, 2.52] and aPR: 0.93 [0.14, 6.43]) but higher TNF- (aPR: 1.93 [0.77, 4.84]). In summary, this study found no clear correlation between endometriosis diagnosis, staging, typology and inflammatory markers IL-6, IL-8, and TNF-. Whether endometriosis severity or typology is associated with TNFshould be explored in future studies with adequate power and more representative samples.

Women's Reproductive History Before the Diagnosis of Incident Endometriosis

Buck Louis GM et al., 2016 · J Womens Health (Larchmt) · Free full text on PubMed Central

Endometriosis is a gynecologic disease reported to be associated with infertility and, possibly, adverse pregnancy outcomes. While considerable research focuses on pregnancy outcomes following diagnosis and/or treatment, few data actually describe women's reproductive history before diagnosis for a more complete understanding of endometriosis and reproduction. The study sample comprised 473 women (aged 18-44 years) undergoing laparoscopies or laparotomies, irrespective of surgical indication at 14 clinical sites, during the period 2007-2009. Upon enrollment and before surgery, women were queried about pregnancy intentions and the time required to become pregnant for planned pregnancies. Endometriosis was defined as surgically visualized disease. Using discrete time survival analysis, we estimated fecundability odds ratios (FORs) and 95% confidence intervals (CIs) to assess time to pregnancy (TTP) after adjusting for potential confounders (age, body composition, cigarette smoking, site). Generalized estimating equations accounted for multiple pregnancy attempts per woman. FORs ResultsApproximately 66% and 69% of women with and without endometriosis, respectively, reported having a planned pregnancy before surgery, respectively. After adjustment, an endometriosis diagnosis was associated with ≈29% reduction in fecundity or a longer TTP across all pregnancy-trying attempts (adjusted FOR = 0.71; 95% CI 0.46-1.10). While FORs were consistently ConclusionsWomen with endometriosis had a longer TTP than unaffected women, irrespective of disease severity, although the findings did not achieve significance. Prior reproductive history may be informative for predicting fecundity and pregnancy outcomes following diagnosis/treatment.

Endometriosis Typology and Ovarian Cancer Risk

Barnard ME et al., 2024 · JAMA · Free full text on PubMed Central

Endometriosis has been associated with an increased risk of ovarian cancer; however, the associations between endometriosis subtypes and ovarian cancer histotypes have not been well-described. To evaluate the associations of endometriosis subtypes with incidence of ovarian cancer, both overall and by histotype. DESIGN, SETTING, And Population-based cohort study using data from the Utah Population Database. The cohort was assembled by matching 78 893 women with endometriosis in a 1:5 ratio to women without endometriosis. Exposures: Endometriosis cases were identified via electronic health records and categorized as superficial endometriosis, ovarian endometriomas, deep infiltrating endometriosis, or other. Main Outcomes and Measures: Estimated adjusted hazard ratios (aHRs), adjusted risk differences (aRDs) per 10 000 women, and 95% CIs for overall ovarian cancer, type I ovarian cancer, and type II ovarian cancer comparing women with each type of endometriosis with women without endometriosis. Models accounted for sociodemographic factors, reproductive history, and past gynecologic operations. In this Utah-based cohort, the mean (SD) age at first endometriosis diagnosis was 36 (10) years. There were 597 women with ovarian cancer. Ovarian cancer risk was higher among women with endometriosis compared with women without endometriosis (aHR, 4.20 [95% CI, 3.59-4.91]; aRD, 9.90 [95% CI, 7.22-12.57]), and risk of type I ovarian cancer was especially high (aHR, 7.48 [95% CI, 5.80-9.65]; aRD, 7.53 [95% CI, 5.46-9.61]). Ovarian cancer risk was highest in women with deep infiltrating endometriosis and/or ovarian endometriomas for all ovarian cancers (aHR, 9.66 [95% CI, 7.77-12.00]; aRD, 26.71 [95% CI, 20.01-33.41]), type I ovarian cancer (aHR, 18.96 [95% CI, 13.78-26.08]; aRD, 19.57 [95% CI, 13.80-25.35]), and type II ovarian cancer (aHR, 3.72 [95% CI, 2.31-5.98]; aRD, 2.42 [95% CI, -0.01 to 4.85]). Conclusions and Relevance: Ovarian cancer risk was markedly increased among women with ovarian endometriomas and/or deep infiltrating endometriosis. This population may benefit from counseling regarding ovarian cancer risk and prevention and could be an important population for targeted screening and prevention studies.