Reproductive Health Consequences of Per- and Polyfluoroalkyl Substances and Microplastics in Mid-life Women: A Systematic Review of Emerging Evidence

Mid-life women, broadly defined as those in the late reproductive through early postmenopausal years (approximately 35–65 years of age),[ 1 ] experience critical transitions in reproductive health. This life stage encompasses the menopausal transition, characterized by hormonal fluctuations, declining ovarian reserve, and the end of natural fertility. Understanding environmental risk factors that may disrupt reproductive health during mid-life is crucial, as midlife represents a window where exposures could accelerate ovarian aging or exacerbate gynecologic conditions. Among emerging concerns are microplastics and per- and polyfluoroalkyl substances (PFAS), two pervasive pollutants with potential endocrine-disrupting effects. Microplastics (plastic particles <5 mm) have been detected in human tissues, including placentas[ 2 ] and even bloodstream,[ 3 ] raising alarms about chronic internal exposure. Animal studies indicate that micro- and nanoplastics can induce oxidative stress, inflammation, and reproductive toxicity in female animals,[ 4 ] but human evidence remains nascent. PFAS, a class of highly persistent organic pollutants used in industrial and consumer products (e.g., nonstick cookware and firefighting foams), bioaccumulate in humans with serum half-lives of years.[ 5 ] PFAS are known endocrine disruptors and have been linked to adverse reproductive outcomes in experimental models and exposed communities. This systematic review focuses on human studies evaluating reproductive health risks associated with chronic microplastic and PFAS exposures, specifically in mid-life women. We consider a full spectrum of reproductive health metrics relevant to this demographic: hormone levels (e.g., estrogen, FSH), menstrual cycle characteristics, fertility and fecundity, age at menopause, ovarian reserve, and gynecologic conditions such as endometriosis, uterine fibroids, and polycystic ovarian syndrome (PCOS). By synthesizing the evidence from epidemiologic studies, we aim to assess whether chronic exposure to microplastics or PFAS is associated with measurable detriments in mid-life women’s reproductive health. We also identify gaps in knowledge – particularly salient given that midlife women may have decades of cumulative exposure by the time they reach menopausal transition. The review adheres to PRISMA 2020 guidelines and provides a rigorous methodology, including a detailed search strategy, quality appraisal of studies, and assessment of publication bias. Below, we outline our methods and then present the findings, organized by exposure type and outcome, followed by a critical discussion of the implications for women’s health at mid-life.

We conducted a comprehensive literature search to identify human studies assessing reproductive health outcomes in mid-life women (approximately 35–65 years old) in relation to microplastic or PFAS exposure. A professional research librarian was consulted to develop the search strategy. We searched multiple databases – including PubMed, Scopus, Web of Science, and Embase– from inception through April 2025. The search combined keywords and MeSH terms related to microplastics (e.g., ”microplastic,” “nanoplastic,” “plastic pollution”) or PFAS (e.g., ”perfluorinated,” “PFAS,” “PFOA,” “PFOS,” “perfluorochemical”) with terms for reproductive health outcomes (“fertility,” “fecundity,” “menstrual,” “menopause,” “ovarian reserve,” “hormone,” “endometriosis,” “fibroids,” “PCOS,” etc.) and filters for human studies. No language restrictions were applied. We also manually screened reference lists of relevant reviews and included articles for any additional studies. Inclusion criteria were defined a priori as: (1) original human research (observational or interventional) reporting an exposure assessment of microplastics or PFAS (measurement in human tissues or biomonitoring of blood/urine levels, or well-defined environmental exposure); (2) reporting at least one quantitative reproductive health outcome in women (e.g., hormone levels, menstrual cycle parameters, age at menopause, time-to-pregnancy, diagnosis of a gynecologic condition, etc.); (3) with a study population that included mid-life women (we included studies focusing on adult women and extracted results specifically for mid-life age ranges when available). We excluded animal and in vitro studies, studies without specific reproductive health endpoints (e.g., only general health outcomes), and studies lacking relevant exposure data. Where multiple publications reported on the same cohort and outcome, we included the most recent or comprehensive report to avoid duplicate data. Search results from all databases were imported into a reference manager, and duplicates were removed. Titles and abstracts were screened independently by two reviewers against the inclusion criteria. Studies clearly unrelated to both microplastics/PFAS and female reproductive health were excluded at this stage. Full-text articles of remaining citations were retrieved and assessed in detail for eligibility. Any uncertainties or disagreements in inclusion were resolved by discussion or consultation with a third reviewer. The study selection process is illustrated in the PRISMA 2020 flow diagram [ Figure 1 ]. In total, 18 studies met all criteria and were included in the qualitative synthesis [ Figure 1 ]. These comprised epidemiological studies investigating PFAS exposures (the majority of included papers) and the limited human studies on microplastic exposure and female reproductive metrics. PRISMA 2020 flow diagram of study selection We identified 823 records through database searches, of which 123 were duplicates, yielding 700 unique records screened. After title/abstract screening, 630 records were excluded as irrelevant. Seventy full-text articles were assessed for eligibility, and 52 were excluded (e.g., animal studies, or wrong population/outcome), leaving 18 studies that met inclusion criteria for this review. From each included study, we extracted detailed information on: author, year, study design (e.g., cohort, case–control, and cross-sectional), study population characteristics (sample size, age range with focus on mid-life if reported, and location), exposure assessment method (for PFAS: specific compounds measured and biological matrix; for microplastics: sample type and detection method), exposure levels or categories, the reproductive health outcomes measured (e.g., hormone levels, fertility metrics, and diagnoses of conditions), and the key findings (effect estimates or qualitative conclusions regarding association between the exposure and outcome). When available, we recorded adjusted effect estimates (e.g., adjusted odds ratios or hazard ratios) and 95% confidence intervals, as well as which confounding variables were adjusted for. Data were extracted by one reviewer and verified by a second for accuracy. We critically appraised the quality and risk of bias of included studies using the Newcastle–Ottawa Scale (NOS) for observational studies (adapted for cohort and case–control studies as appropriate). This validated tool assesses studies on three domains: selection of participants, comparability of study groups, and exposure/outcome ascertainment. Each study was scored on a scale of 0–9 stars. For cross-sectional studies that did not neatly fit NOS, we applied equivalent criteria focusing on sample representativeness, measurement reliability, and control of confounding. Two reviewers performed quality assessments independently, with discrepancies resolved through consensus. We considered studies with NOS scores ≥7 as “high quality,” 4–6 as “moderate,” and <4 as “low quality.” Key quality issues identified included potential confounding and exposure misclassification, which are discussed in the results. No studies were excluded based on quality; however, the quality ratings were taken into account when interpreting the strength of evidence. Given the heterogeneity of exposures (two distinct pollutant types) and outcomes, a quantitative meta-analysis was not uniformly feasible. We summarized results in a narrative synthesis stratified by exposure type (PFAS and microplastics) and by outcome domain. We constructed summary tables to compare study characteristics and findings [ Table 1 ]. Where multiple studies examined a similar exposure-outcome association (e.g., PFAS and endometriosis), we qualitatively compared their results and noted consistency or discrepancies. We assessed publication bias qualitatively due to the small number of studies per outcome; a funnel plot or Egger’s test was planned if ≥10 studies reported a comparable outcome, but this criterion was not met for any single outcome. We nonetheless considered the likelihood of reporting bias in the literature (e.g., whether smaller studies with null results might be unpublished) in our interpretation. Characteristics of few included human studies on polyfluoroalkyl substances or microplastic exposure and mid-life women’s reproductive health outcomes PFAS: Polyfluoroalkyl substances, PFOS: Perfluorooctane sulfonate, PFOA: Perfluorooctanoic acid, PFNA: Perfluorononanoic acid, FSH: Follicle-stimulating hormone, IVF: In vitro fertilization, PFHxS: Perfluorohexane sulfonate, SEM: Scanning electron microscopy, EDX: Energy dispersive X-ray, MP: Microplastic, LC-MS/MS: Liquid chromatography- tandem mass spectrography, PFTrDA: Perfluroteradecanoic acid

Eighteen studies fulfilled the inclusion criteria, comprising 16 studies on PFAS exposure and 2 studies on microplastic exposure in human mid-life women. Table 1 presents the detailed characteristics and findings of each included study. The PFAS-focused studies were predominantly observational cohorts or case–control studies in various populations (from North America, Europe, and Asia), reflecting the widespread exposure to PFAS and interest in their endocrine-disrupting potential. These studies covered a range of outcomes: menopausal timing and hormonal changes, fertility/fecundity outcomes, and gynecological conditions (including endometriosis, PCOS, and fibroids). Sample sizes for PFAS studies ranged from large population-based cohorts (hundreds to thousands of women) to smaller case-control studies (on the order of 100–500 participants). All PFAS studies assessed exposure through biomonitoring of blood serum or plasma levels of specific PFAS compounds (such as PFOA, PFOS, PFHxS, and PFNA), often focusing on legacy long-chain PFAS. Most accounted for relevant confounders such as age, body mass index (BMI), smoking, and parity in their analyses. In contrast, human microplastic exposure studies in mid-life women are scant. We found only two studies meeting our criteria: one examining microplastics in human ovarian follicular fluid of women (most of whom were in their late 30–40 s) undergoing IVF,[ 4 ] and another that detected microplastic fragments in human placentas from term pregnancies.[ 2 ] Both are pioneering studies highlighting the presence of microplastics in reproductive tissues; however, they were not large epidemiologic studies of health outcomes per se . The follicular fluid study correlated microplastic levels with certain ovarian function markers, while the placental study was primarily a contamination assessment without linking to clinical outcomes. No epidemiologic studies were found that directly evaluated chronic microplastic exposure against reproductive health metrics in mid-life women (e.g., no studies of microplastic load vs. menopause timing were identified). This underscores a major research gap for microplastics relative to PFAS. The strongest and most consistent evidence linking PFAS to mid-life women’s reproductive health pertains to accelerated ovarian aging and earlier menopause. In the large SWAN cohort study, Ding et al . (2022) observed that women with higher serum concentrations of several PFAS experienced significantly earlier natural menopause.[ 6 ] For example, women in the top tertile of PFOA or PFOS had a 16%–21% shorter time to menopause relative to those in the bottom tertile, after adjusting for age and other factors.[ 6 ] This translates to reaching menopause roughly 2 years earlier in high-exposure individuals, an effect magnitude deemed clinically relevant.[ 6 ] Mechanistically, PFAS were associated with elevated FSH levels during the menopausal transition – consistent with PFAS potentially accelerating ovarian follicle depletion. The mediation analysis by Ding et al . found that a modest proportion (up to ~ 27%) of the PFAS effect on menopause timing could be statistically explained by FSH changes.[ 6 ] No mediation through estradiol was seen, suggesting PFAS impacts the ovary upstream (follicular loss triggering higher FSH).[ 6 ] These findings align with PFAS as endocrine disruptors targeting the ovary.[ 6 ] Importantly, this association was observed in a longitudinal study of mid-life women with prospectively determined menopause age, strengthening causal inference. Another analysis from the same SWAN cohort had earlier reported that PFAS exposure was linked to increased odds of being in an elevated FSH/low estradiol status indicative of ovarian insufficiency.[ 6 ] Overall, evidence suggests chronic PFAS exposure may accelerate ovarian aging and hasten the onset of menopause in mid-life women.[ 6 ] This is significant because earlier menopause is itself associated with higher risks of osteoporosis and cardiovascular disease in later life. Beyond menopause, a few studies examined PFAS in relation to menstrual cycle characteristics in women still menstruating. Lum et al . in the LIFE cohort found subtle alterations in cycle length associated with PFAS.[ 10 ] PFOA was linked to slightly shorter cycles and PFDeA to slightly longer cycles, though differences were on the order of only 2%–3%.[ 10 ] These small shifts (e.g., a couple of days difference in cycle length) suggest PFAS might have mild effects on cycle dynamics, but results were not entirely consistent across compounds. Other epidemiologic research has shown mixed findings: some cross-sectional studies reported higher PFAS levels correlating with increased odds of irregular menstrual cycles or anovulation, while others found no association.[ 11 ] In our review, after accounting for more robust longitudinal data, there is suggestive but not conclusive evidence that PFAS exposures can disrupt menstrual regularity or hormone fluctuations before menopause. It is plausible that PFAS, by interfering with ovarian function, could manifest as cycle length changes or irregular menses in mid-life, but more targeted studies are needed for confirmation. While our review focuses on mid-life, it is notable that many mid-life women may still desire fertility (or have late pregnancies). PFAS exposure has been examined in women of reproductive age for its effects on fertility. Cohen et al . (2023) provide strong evidence that PFAS reduces fertility prospects: in women attempting pregnancy (mean age ~ 30, some of whom would be in their late 30 s), elevated PFAS markedly lowered the likelihood of conception and live birth within 12 months.[ 9 ] Specifically, women with higher quartiles of PFOS, PFDA, and related PFAS had 10%–20% prolonged time-to-pregnancy and around 30% lower odds of achieving pregnancy each cycle.[ 9 ] When considering all PFAS as a mixture, those in the highest exposure group had roughly a 40% lower chance of conceiving and delivering in 1 year compared to the lowest exposure group.[ 12 ] These findings are supported by earlier studies in various populations. For instance, a 2014 European study (Zurub et al .) reported that higher PFOS/PFOA levels were associated with longer time-to-pregnancy among couples in Greenland and Europe.[ 12 ] Another study in Texas noted that women with higher PFAS took longer to become pregnant, suggesting subfecundity associated with PFAS. The biological plausibility lies in PFAS’ interference with hormones involved in ovulation and implantation. Furthermore, PFAS have been implicated in diminished ovarian reserve: one study found that women with higher PFOS/PFOA had lower levels of anti-Müllerian hormone (AMH, a marker of ovarian reserve), although results on AMH have been inconsistent.[ 10 ] Collectively, for women in their late reproductive years (e.g., late 30s), PFAS exposure might make it more difficult to get pregnant and could accelerate the age-related decline in fertility. It is worth noting that by the time women reach their mid-40s, natural fertility is already low; however, PFAS could further compromise any remaining fertility or necessitate longer time and assistance to conceive. A growing body of evidence links PFAS to hormone-driven gynecological disorders. PCOS and uterine fibroids are two prevalent conditions in mid-life or approaching mid-life. The Swedish cohort by Hammarstrand et al . demonstrated a clear positive association between high lifetime PFAS exposure (via contaminated drinking water) and PCOS risk.[ 7 ] Women aged 20–50 from the exposed town had more than double the risk of PCOS compared to those unexposed.[ 7 ] PFAS are known to have androgen-disrupting properties, which could plausibly contribute to PCOS pathophysiology (a syndrome characterized by excess androgens, ovarian cysts, and irregular cycles). That study also hinted at a possible increase in fibroid (leiomyoma) incidence with PFAS (HR ~ 1.3).[ 7 ] Fibroids are estrogen-sensitive benign tumors of the uterus commonly occurring in 30s–50s; if PFAS affect estrogen pathways, they could promote fibroid development, though the evidence here was borderline. The relationship between PFAS and endometriosis has been investigated in multiple human studies with strikingly consistent findings. Endometriosis, an estrogen-dependent inflammatory condition where uterine lining tissue grows outside the uterus, often affects women in their reproductive years and can persist into mid-life. The ENDO study was one of the first to report significantly higher odds of endometriosis among women with elevated PFAS.[ 5 ] Particularly, PFOA and PFOS showed strong associations with surgically confirmed disease (with nearly 2-fold or greater odds).[ 5 ] This was notable as it accounted for confounders and was a well-designed case–control study. Our review identified a newer 2024 study which corroborated these findings in a Spanish population: certain PFAS (PFTrDA, and to a lesser extent PFHxS) were linked to increased endometriosis risk.[ 8 ] Although not all PFAS chemicals showed effects, the consistency of at least some PFAS being elevated in endometriosis patients across studies and populations is compelling. The biological mechanism may involve PFAS-induced inflammatory pathways or immune dysfunction that facilitate endometrial tissue implantation outside the uterus.[ 9 ] It is also worth noting that reverse causality is unlikely here (i.e., endometriosis itself probably does not raise PFAS levels) because PFAS are exogenous persistent pollutants. Thus, the epidemiologic evidence points to PFAS as a risk factor for endometriosis, a condition that can significantly impact quality of life and fertility in mid-life women. In summary, PFAS exposures in humans have been associated with a spectrum of adverse reproductive outcomes in mid-life women: earlier menopause (ovarian aging), altered menstrual function, reduced fertility, and higher incidence of hormonally-mediated disorders such as PCOS and endometriosis. The associations are biologically plausible given PFAS’ known endocrine-disrupting properties and persistent nature. High-quality cohort data (e.g., SWAN, S-PRESTO) strengthen confidence in these links, though some inconsistencies and the challenge of measuring long-term exposure accurately mean that causality, while strongly suggested, is not conclusively proven for every outcome. Nonetheless, the convergence of evidence raises significant concern that chronic PFAS exposure is an unrecognized contributor to female reproductive aging and dysfunction. In contrast to PFAS, research on microplastics and human reproductive health is in its infancy. We found no large epidemiological studies analogous to the PFAS literature; instead, current knowledge comes from small-scale detection studies and theoretical considerations. The two included studies provide proof that microplastics are present in human reproductive environments, but direct links to health outcomes are tentative. The study by Montano et al . offered the first direct evidence of microplastics in human ovarian follicular fluid, which bathes developing eggs.[ 4 ] This is a key finding as it demonstrates that microplastics (likely originating from chronic environmental exposure via ingestion or inhalation) can accumulate in the very compartment of the ovary critical for reproduction. The detected concentrations (on the order of thousands of particles per milliliter) and the high detection frequency (78% of patients) indicate that exposure is not rare. While the sample was small (18 women), the significant correlation between microplastic count and FSH levels[ 4 ] raises a red flag: higher FSH suggests reduced ovarian reserve or function, as the body is needing to secrete more FSH to stimulate the ovaries. This finding, albeit preliminary, hints that women with greater microplastic burden might be experiencing more ovarian aging or dysfunction (similar in effect to an older chronological age or toxins that diminish the follicle pool). However, it must be emphasized that no differences were seen in immediate IVF outcomes in this study,[ 4 ] for example, the number of eggs retrieved or fertilization success did not clearly vary with microplastic levels. With such a limited sample, the power to detect subtle fertility effects was low. Future studies with larger IVF cohorts could further examine if microplastics in follicular fluid correlate with egg quality, embryo development, or pregnancy rates. If a causal relationship exists, microplastics could impair oocyte competence through inflammatory or oxidative mechanisms in the follicle. The “Plasticenta” study (Ragusa et al . 2021) demonstrated microplastics crossing the placenta barrier.[ 2 ] This is directly relevant to mid-life women in the context of pregnancy and fetal health. Many women now become pregnant in their late 30s or 40s (mid-life), meaning their cumulative microplastic exposure is higher by the time of pregnancy. The finding that microplastic fragments were lodged in both maternal and fetal sides of the placenta[ 2 ] suggests potential for fetal exposure during a critical developmental period. While no adverse pregnancy outcomes were reported in those mothers (all had normal healthy babies), the mere presence of foreign plastic particles is concerning. Microplastics could induce local inflammation in the placenta or contribute to oxidative stress, which in theory might affect nutrient exchange or increase the risk of complications. Research in animals has linked maternal nanoparticle exposure to smaller offspring and placental inflammation.[ 13 ] Thus, an important question is whether higher microplastic loads in pregnant women correlate with outcomes such as lower birthweight, preterm birth, or preeclampsia. As of this review, such epidemiologic data do not exist – an urgent area for future human studies. Beyond these studies, indirect evidence raises additional concerns. A recent cross-sectional study found that nearly 90% of tested human blood samples contained microplastics, and higher blood microplastic levels were associated with elevated inflammatory and coagulation markers.[ 3 ] Chronic systemic inflammation or hypercoagulability could, in turn, impact reproductive health, for instance, by impairing endometrial receptivity or increasing miscarriage risk. Indeed, chronic inflammation is a known contributor to conditions like endometriosis. It is conceivable that microplastic exposure, through ongoing immune activation, might predispose women to such conditions, though direct evidence is lacking. We also note emerging data of microplastics being found in human breastmilk and even in adult human lung tissue, underscoring that mid-life women are ubiquitously exposed in daily life (via air, water, food). Thus, while the human epidemiologic evidence linking microplastics to reproductive outcomes is extremely sparse at present, the widespread presence of microplastics in human bodies is established, and there are plausible pathways (inflammation, endocrine disruption from plastic additives leaching) by which they could impair reproductive health. In summary, microplastics represent a potential emerging threat to mid-life women’s reproductive health, but current evidence is largely limited to the detection of these particles in reproductive tissues. The one study suggesting a correlation with ovarian hormone (FSH) is intriguing but insufficient to draw firm conclusions. No studies to date have evaluated chronic microplastic exposure against clinical endpoints like infertility, age at menopause, or gynecologic disease in women. Therefore, at this time, we can only highlight the concern and the need for targeted research. Mid-life women, having accumulated more exposure over time, could be at greater risk of microplastic-related effects if those exist. This is an important frontier for environmental reproductive epidemiology. The overall quality of the included studies was moderate to high, with some distinctions between PFAS and microplastic studies. Using the NOS criteria, most PFAS studies scored in the 6–8 range (out of 9). They generally had strong selection and exposure assessment (PFAS measured in blood with validated assays). Cohort studies such as SWAN and S-PRESTO were particularly robust, with prospective design and rigorous confounder adjustment, earning high-quality marks. The case-control studies (e.g., on endometriosis) had some risk of selection bias (hospital-based controls in one study) but were otherwise well-controlled; for example, Buck Louis et al . matched on age and location and confirmed endometriosis surgically, which strengthens validity.[ 5 ] A recurring limitation in PFAS studies was the possibility of reverse causality or confounding by physiology, for example, women with poor ovarian function might have different PFAS toxicokinetics (some PFAS are eliminated via menstrual blood loss, so cessation of menses could raise PFAS levels, making cause–effect harder to untangle). One analysis explicitly addressed this by performing a bias analysis and concluded that reverse causality was unlikely to fully explain the earlier menopause finding.[ 5 ] Most PFAS studies adjusted for major confounders (age, BMI, smoking, parity), but fewer adjusted for socio-economic status or co-exposures to other chemicals, which could introduce residual confounding. Nonetheless, given PFAS are distributed fairly uniformly in populations, confounding is not expected to be large. The microplastic studies were of more limited quality by epidemiological standards– Montano et al . (2025) was essentially a small cross-sectional case series without a comparison group, and Ragusa et al . (2021) had an N of 6. We did not assign NOS scores to these as they did not fit well; instead, we qualitatively noted that while laboratory detection methods were state-of-the-art (reducing measurement bias), the study designs lacked power and the ability to control confounding. The follicular fluid study did note precautions to avoid sample contamination (a critical issue for microplastics research),[ 4 ] which is a strength. However, given the novelty, these studies serve more as proof-of-concept and carry a high risk of various biases (selection bias, given IVF patients may not represent general population; and measurement limited to presence vs. absence of pregnancy within one cycle, which may not capture long-term fertility impact). In terms of publication bias, formally assessing it was challenging due to the limited number of studies per topic. We did not have enough comparable studies to draw a funnel plot for any single outcome. However, qualitatively, we suspect some publication bias is present. For PFAS, research into reproductive outcomes is fairly recent and often driven by positive findings – it is possible that null findings (especially from smaller studies) went unpublished or were harder to find. The fact that multiple studies from different groups have independently found similar links (e.g., PFAS and endometriosis, PFAS and menopause) provides some reassurance that the literature is not exclusively cherry-picked positive results. For microplastics, the field is so new that the first studies to appear all highlight detection of microplastics; if any studies had looked and found none, those might not have been published. In additition, outcomes such as “no effect on IVF outcomes” might be deemphasized in reporting relative to the striking discovery of microplastics in tissue. Therefore, the current literature may over-represent the presence of microplastics and potential harm signals simply because of the novelty factor. We note this as a caution: as the field evolves, more rigorous and possibly larger studies (even if showing smaller or no effects) will balance the picture.

Mid-life women’s reproductive health may be adversely affected by chronic exposure to environmental pollutants such as PFAS and microplastics. Human studies on PFAS provide substantial evidence that these “forever chemicals” can disrupt endocrine function, leading to outcomes such as earlier menopause, altered menstrual cycles, reduced fertility, and increased risk of gynecologic disorders (endometriosis, PCOS). These findings underscore PFAS as important determinants of fesssmale reproductive aging and health, warranting public health actions to minimize exposure. In contrast, human evidence on microplastics is still limited to the demonstration of their presence in reproductive organs; definitive links to health outcomes have yet to be established. However, given the omnipresence of microplastics and suggestive early data (e.g., correlation with ovarian FSH levels), prudence is advised. Mid-life women today are navigating their reproductive transitions in an era of unprecedented environmental chemical exposure. This review highlights the need to integrate environmental considerations into women’s health research and healthcare. Protecting women from harmful exposures through policy, lifestyle guidance, and further research is essential for improving reproductive health outcomes and healthy aging for current and future generations. There are no conflicts of interest.

This systematic review synthesizes the current human evidence on two classes of ubiquitous environmental contaminants PFAS and microplastics in relation to mid-life women’s reproductive health. Overall, the evidence is much more developed for PFAS, which has been studied for over a decade in epidemiology, whereas for microplastics the evidence is only emerging. Despite this disparity, both pollutants raise significant concern as chronic exposures that could potentially accelerate reproductive aging or impair reproductive function in women. The reviewed data provide a converging signal that PFAS are detrimental to various aspects of women’s reproductive health. One of the most striking findings is the association between higher PFAS exposure and earlier age of natural menopause.[ 6 ] From a public health perspective, a shift of even 1–2 years earlier in menopause across a population could have sizeable implications, increasing risks for postmenopausal health issues and shortening the reproductive lifespan. The consistency of this finding with mechanistic expectations (PFAS as ovarian toxicants) is notable. Experimental animal studies support that certain PFAS can induce ovarian follicle loss and interfere with steroidogenesis. Our review shows human data align with this: higher PFAS correlated with higher FSH (a hallmark of ovarian aging) and lower estrogen in mid-life.[ 6 ] This adds PFAS to the list of environmental factors (alongside smoking, for instance) that are known to hasten ovarian aging. Clinicians caring for mid-life women may need to be aware that environmental exposures contribute to menopausal timing variability. Women with high PFAS (such as those from contaminated communities or with occupational exposure) might face premature ovarian insufficiency or earlier transition, which could warrant monitoring or earlier intervention (e.g., bone density screening at a younger age). PFAS exposure was also linked to reduced fertility and fecundability, as evidenced by longer times to conceive and possibly higher miscarriage rates. Although our focus was mid-life, these findings are relevant because many women now attempt pregnancy in their late 30 s or 40 s. A compounding effect of age and PFAS could further lower fertility. One included study in our review noted PFAS exposures were associated with a trend towards increased miscarriage (though we did not detail it earlier, Cohen et al . in 2020 found elevated odds of pregnancy loss with higher PFAS.[ 9 ] Taken together, PFAS may affect both ends of the reproductive spectrum– from making it harder to get pregnant to causing menopause to occur sooner. This double impact can significantly compress the reproductive period. Importantly, PFAS are often called “forever chemicals” due to their persistence; mid-life women today likely carry body burdens of PFAS from decades of cumulative exposure. Thus, whatever effects PFAS have are a result of chronic, long-term interactions with the endocrine system. Gynecological health outcomes such as endometriosis and PCOS further highlight PFAS as endocrine disruptors. It is rare in environmental epidemiology to see such a consistent association as that observed between PFAS and endometriosis across multiple studies and geographies.[ 5 8 ] While more research is needed to establish causality (including prospective studies measuring PFAS prior to endometriosis development), the current evidence suggests a plausible link. If causal, reducing PFAS exposure could potentially be part of preventive strategies for endometriosis a provocative idea since endometriosis is traditionally not thought of as an environmental disease. PCOS evidence is more preliminary, but if confirmed, it indicates PFAS might influence androgenic pathways as well.[ 7 ] One mechanistic hypothesis is that PFAS act as agonists or antagonists to nuclear receptors (such as PPARs or estrogen receptors) which play roles in metabolism and ovarian function. For example, PFOA is known to activate PPAR-alpha, which could disrupt ovarian granulosa cell function. PFAS might also indirectly perturb reproductive health through the thyroid gland – PFAS can reduce thyroid hormone levels, and thyroid disorders can affect menstrual cycles and fertility. Our review did not specifically cover thyroid outcomes, but it’s an interlinked piece worth acknowledging. Although human data are scant, there is cause for concern. Microplastics themselves are particle pollutants, but an often-overlooked aspect is that they can carry sorbed chemicals (like phthalates, BPA, or even PFAS) and can leach monomers and additives. So microplastic exposure could effectively also be chemical exposure. A mid-life woman’s chronic ingestion of microplastics (via, say, bottled water or seafood) means a continual low-dose exposure to the cocktail of chemicals on and in those plastics. This complicates teasing out effects – is it the particle causing inflammation, or the chemical causing endocrine disruption, or both synergistically? The presence of microplastics in ovarian follicular fluid and placenta is analogous to having a persistent foreign body in critical sites. One can draw a parallel with air pollution particles: we know inhaled fine particulate matter can enter circulation and cause systemic inflammation and cardiovascular risk. Microplastics, being larger, may get trapped in organs like lymph nodes, placenta, or remain in follicular fluid, potentially causing local oxidative stress.[ 14 ] The ovary is highly sensitive to oxidative damage (as seen in chemotherapy effects on ovaries, for instance). If microplastics induce oxidative stress in follicles, that could accelerate follicle loss or impair oocyte quality, leading to earlier menopause or reduced fertility. These are hypotheses that now need rigorous testing. It is also worth discussing that microplastics exposure is practically universal, but exposure levels can vary. People who consume more bottled water, seafood, or have high contact with dust might have higher internal loads. Mid-life women in coastal areas or certain occupations could be at higher risk. Our review highlights that currently, we lack epidemiological studies that quantify individual microplastic exposure (there is no standard blood test yet for microplastic load in persons) and relate it to outcomes. Developing biomarkers of microplastic exposure (perhaps measuring common polymer types in blood) would enable such studies. There is an urgency to do this, as microplastic pollution is only increasing globally. By focusing exclusively on human studies, we synthesized directly relevant evidence for public health and clinical considerations. We also comprehensively covered multiple reproductive outcomes in mid-life, providing a broad perspective on how these exposures might impact women at different stages of the mid-life transition (from late fertility to post menopause). The systematic methodology (multi-database search, clear inclusion criteria, quality appraisal) adds rigor and minimizes bias in our conclusions. However, a limitation is that the heterogeneity of outcomes precluded meta-analysis; thus, we could not generate summary effect sizes for, say, “PFAS and menopause age.” In addition, the paucity of microplastic studies limits any conclusions on that front – our review for microplastics is more narrative and speculative, relying on very few data points. Another limitation is potential publication bias in the available literature, as discussed. Finally, exposure assessment differences (e.g., older studies measured legacy PFAS like PFOS/PFOA that have since been phased out and replaced by newer PFAS; microplastic studies each used different detection methods) mean that comparisons across studies have uncertainty. Despite these, the review provides a timely synthesis as regulatory and scientific communities grapple with understanding how novel environmental exposures intersect with women’s health. The findings for PFAS bolster the rationale for policies to limit PFAS exposure, especially among vulnerable groups such as women of childbearing age. Some jurisdictions have begun banning certain PFAS in food packaging and firefighting foam. Our review adds reproductive aging to the list of adverse outcomes potentially mitigated by reducing PFAS emissions and exposures. Clinicians might also consider discussing environmental exposure reduction (for instance, avoiding PFAS-containing products, using water filters in contaminated areas) as part of counselling for women with unexplained early ovarian insufficiency or those planning pregnancies later in life. For microplastics, while evidence is early, the precautionary principle would suggest efforts to reduce unnecessary ingestion of microplastics (such as reducing use of plastic containers for hot food, advocating for clean drinking water free of plastic debris, etc.), given the potential risks identified. There is a clear need for more research on microplastics and female reproductive health. Longitudinal cohort studies that follow mid-life women with measured microplastic exposure (perhaps via advanced imaging or blood analysis techniques) and track their menopausal timing or incidence of conditions like fibroids would be invaluable. For PFAS, future research should explore underlying mechanisms in humans for example, studying hormonal changes in real time or genetic susceptibility (why some women with high PFAS have much earlier menopause and others do not). In addition, as PFAS are a broad class, more work on which specific compounds are most harmful (many studies pointed to PFOA, PFOS, PFNA as culprits; what about newer PFAS?) will help regulatory focus. Interventional studies are also important: if PFAS removal (chelation or exposure cessation) in high-exposed women leads to improved reproductive markers, that would be powerful evidence. Finally, combined exposures should be studied – women are exposed to PFAS, microplastics, and other endocrine disruptors simultaneously. Future studies should attempt to account for mixtures, since real-world exposures do not happen in isolation.