Women with recurrent pregnancy loss report more depression than men
Women with recurrent pregnancy loss had more moderate or severe depression than men. Pooling three cross-sectional studies, a 2023 meta-analysis found it in about 20 out of 100 women against 7 out of 100 men. Four studies with controls, women trying to conceive, gave about 6 out of 100 against 2 out of 100.
Key Findings
Across four studies, moderate or severe depression affected 93/1565 (5.9%) women with recurrent pregnancy loss against 84/3794 (2.2%) controls: OR 3.77, 95% CI 2.71–5.23, I2 0%.
Across three cross-sectional studies, moderate or severe depression affected 113/577 (19.5%) women and 33/446 (7%) men who experienced recurrent pregnancy loss: OR 4.63, 95% CI 2.95–7.25, I2 0%.
Stress on the Perceived Stress Scale was higher in women with loss than in controls (42% versus 23.1%; 28.6% versus 23.1%) and than in men (28.6% versus 10.6%, one study).
Three studies found higher anxiety in women with loss than in controls (4% versus 1.4%; 2% versus 1.4%; 9.3% versus 5.4%). Two found 25% versus 4% and 47.7% versus 19.1% against men.
Interpretation
The review pooled observational studies, so the results show an association at one point in time and cannot show that the losses caused the depression. Depression, stress and anxiety came from self-reported questionnaires without a clinical diagnosis. The authors rate the quality of evidence low to very low on the GRADE system. The studies defined recurrent loss as two or three losses, and two studies used depression and anxiety scales not validated in this population. Two studies shared one control group. Stress and anxiety came from two or three studies each and were described without pooling. The search ran to February 2022.
RRM Context
Restorative reproductive medicine centers the couple and searches for the cause of each loss. The review compared depression, stress and anxiety in women with loss against controls and against men. It evaluated no causes of loss and no treatments. The authors advise gynecologists, often the first to see these couples, to recognize effects on both partners and refer both to a mental health specialist. The specialist should tailor counseling by sex. They raise hypotheses linking inflammation and abnormal intestinal permeability to depression in recurrent loss; the review tested neither.
Our editorial summary of this paper, not the article's abstract.
Abstract
The aim of the present study is to perform a systematic review and meta-analysis on depression, stress and anxiety in women who experienced recurrent pregnancy loss (RPL) compared to controls and to men who experienced RPL. The pooled results showed a higher level of moderate/severe depression among women who experienced RPL compared to controls (5359 women, random effects model, odds ratio (OR) 3.77, 95% Confidence Interval (CI) 2.71-5.23, p < 0.00001, I2 0%). Anxiety and stress levels were also higher among women experiencing RPL compared to controls. The pooled results showed a higher level of moderate/severe depression in women who experienced RPL compared to men who underwent the same experience (113/577 (19.5%) women versus 33/446 (7%) men versus random effects model, OR 4.63; 95% CI 2.95-7.25, p < 0.00001 I2 0%). Similarly, higher levels of stress and anxiety in women experiencing RPL compared to men experiencing RPL were described. Women who experienced RPL showed higher rates of moderate-severe depression, stress and anxiety compared to both controls and men who experienced RPL. Healthcare professionals should implement screening for anxiety and depression and social support for both partners and support them in dealing with RPL according to sex-specific responses to this stressful event.
Genetic variability within the follicle-stimulating hormone (FSH)-related genes might contribute to phenotypic heterogeneity in patients with Klinefelter syndrome (KS), yet its clinical impact on sperm retrieval remains unclear.
To investigate the association between FSHB c.211 G > T and FSHR polymorphisms (c.2039 A > G and c.29 G > A) and hormonal parameters, as well as their potential role in predicting sperm retrieval rate (SRR) in patients with KS undergoing testicular sperm extraction (TESE).
A retrospective cohort of patients with KS was analyzed. Only subjects not receiving testosterone replacement therapy were included (n = 417). Hormonal, anthropometric, and clinical variables were compared across genotypes using nonparametric tests. Additive genetic models were applied to evaluate allele-dose effects. Multivariable logistic regression was performed to identify independent predictors of SRR. Predictive performance of clinical and combined clinical-genetic models was assessed using ROC curve analysis.
FSHB and FSHR genes polymorphisms were associated with variations in serum FSH concentrations, confirming a modulatory role of the FSH-related genes. In additive modeling, the FSHR c.29 G > A polymorphism emerged as an independent predictor of SRR (adjusted OR: 0.29; 95% CI, 0.09-0.97), whereas FSHB c.211 G > T showed a nonsignificant trend. The inclusion of genetic variants modestly improved predictive accuracy compared with clinical variables alone, as demonstrated by ROC analysis.
Genetic variants within the genes involved in FSH action might contribute incremental information for the prediction of sperm retrieval in patients with KS. While the overall predictive gain remains moderate, additive genetic modeling highlights a potential allele-dose effect of FSHR c.29 G > A on reproductive outcome, supporting a role for integrated clinical-genetic assessment in this population, although external validation remains required.
Klinefelter syndrome (KS) is characterized by marked phenotypic heterogeneity that might be influenced by genetic modifiers, including androgen receptor (AR) repeat length (CAGn and GGCn). The clinical relevance of these repeat lengths in patients with KS before testosterone replacement therapy (TRT) remains unclear.
To investigate the association between AR repeat length and anthropometric, hormonal, metabolic, and reproductive parameters in a well-characterized cohort of untreated adult patients with KS.
In this cross-sectional single-center study, 214 men with classical 47, XXY karyotype were evaluated prior to TRT. Clinical, biochemical, and reproductive parameters were analyzed according to AR CAGn and GGCn repeat length. Nonparametric tests, multivariable linear and logistic regression models, and interaction terms between CAGn and GGCn were tested. Standardized beta coefficients were used to compare the relative contribution of AR repeat length with major clinical determinants.
In unadjusted analyses, CAG repeat length was associated with estradiol concentrations, whereas GGC repeat length showed associations with hematocrit, platelet count, and total cholesterol. However, most associations were characterized by small effect sizes and did not persist after multivariable adjustment for possible confounders (age, BMI, and total testosterone levels). Moreover, AR repeat length was not associated with sperm retrieval rate. Standardized beta analyses demonstrated that testosterone levels, BMI, and age accounted for the largest proportion of phenotypic variability, whereas CAGn and GGCn repeat length had minimal roles.
In untreated patients with KS, AR repeat length (CAGn and GGCn) appears to have a limited clinical impact compared with classical endocrine and metabolic determinants. These findings suggest that phenotypic variability in KS might be primarily driven by chromosomal aneuploidy and primary testicular dysfunction rather than AR repeat length.
Graziani A et al., 2026·Journal of clinical medicine·Free full text on PubMed Central
Erectile dysfunction (ED) is increasingly recognized as an early manifestation of systemic vascular disease and might represent a window for cardiovascular risk assessment. Dynamic penile colour Doppler ultrasound (PCDU) provides quantitative arterial and venous parameters that could reflect subclinical vascular impairment. We investigated the association between PCDU parameters and estimated cardiovascular risk in men with ED. In this single-center retrospective observational study, 275 men undergoing PCDU for ED were evaluated. Clinical characteristics, biochemical data, and QRISK3 10-year cardiovascular risk scores were collected. Mean peak systolic velocity (PSV), end-diastolic velocity (EDV), and resistive index (RI) were analyzed. Correlation analyses, logistic regression using a QRISK3 ≥ 10% threshold, linear regression models, age-stratified analyses, and receiver operating characteristic (ROC) curve analyses were performed. Patients with impaired PSV (<35 cm/s) were older and exhibited higher QRISK3 scores and a greater prevalence of diabetes mellitus and previous cardiovascular events. Mean PSV was inversely correlated with QRISK3 (r = -0.203, p < 0.01) and was associated with higher cardiovascular risk categories in unadjusted logistic regression (β = -0.016, p = 0.048), but not after adjustment for age and diabetes mellitus. ROC analysis showed modest discrimination of increased cardiovascular risk (AUC = 0.60). The addition of PSV to a model including age and diabetes resulted in minimal improvement in discrimination (AUC 0.966 vs. 0.968). Age-stratified analysis demonstrated a significant association between lower PSV and higher cardiovascular risk only in patients ≤60 years. A progressive increase in QRISK3 was observed according to the number of abnormal Doppler parameters (p = 0.013). PCDU parameters reflect the overall cardiovascular risk burden in men with ED. Although not independent predictors beyond traditional risk factors, penile Doppler abnormalities might identify a vascular phenotype associated with higher estimated cardiovascular risk, particularly in younger individuals. These findings support the role of comprehensive vascular assessment in selected patients with ED.
Barbato M et al., 2026·Frontiers in Reproductive Health·Free full text on PubMed Central
Couple infertility is a common clinical condition that is too often treated with assisted reproductive techniques (ARTs) without a proper evaluation of both male and female factors. To improve the likelihood of natural conception, fertility awareness methods (FAMs) are widely used. We performed a multicenter prospective study enrolling couples with primary idiopathic infertility who were seeking natural conception. Participants were followed for 12 months using FAMs, and their outcomes were compared with those of couples who only used ARTs. The aim of our study was to evaluate the pregnancy rate after 12 months among couples with idiopathic infertility using FAMs compared with those who immediately pursued ARTs. We evaluated 41 couples in the FAM group and 56 couples in the ART group. In the FAM group, we reported a pregnancy rate (PR) of 51.22%. Among women aged <34 years, we reported a PR of 90.9%, while it decreased to 36.7% among women aged 35-39 years. In the ART group, 10 couples achieved pregnancy (PR 17.8%). Within this group, we reported a PR of 30% among women aged <34 years and 17.4% among women aged 35-39 years. After 12 months of unprotected intercourse without spontaneous conception in women younger than 35 years or after 6 months in women aged 35-39 years, couples should undergo a complete multidisciplinary diagnostic evaluation involving both the male and female partners. If a diagnosis of idiopathic infertility is established at the end of this process, couples (especially younger ones) may be advised to wait an additional 12 months while using FAMs, as no advantage has been observed with direct access to ARTs. They could then be referred to ART if a spontaneous pregnancy is not achieved during this period.
Related research
Infertility Distress · Anxiety and Depression in Infertility
Salari N et al., 2024·Archives of Gynecology and Obstetrics·Free to read
In recent years, the global prevalence of infertility has increased among women and is considered as a public health concern. One of the impacts of infertility is mental health problems in the patients, which can lead to complications such as stress, anxiety, and depression. The aim of this study is to investigate the global prevalence of major depressive disorder, general anxiety, stress, and depression in infertile women through a systematic review and meta-analysis. To identify studies that have reported the prevalence of major depressive disorder, generalized anxiety, stress, and depression in infertile women, the PubMed, Scopus, Web of Science, Embase, ScienceDirect, and Google Scholar repositories were systematically searched. Articles published up until February 2023 were included, while no lower time limit was imposed in the search strategy. Heterogeneity of studies was examined using the I2 test and, thus, random-effects model was used to perform the analysis. Data analysis was conducted within the Comprehensive Meta-Analysis (v.2) software. In the review of 44 studies with a sample size of 53,300 infertile female patients, the overall prevalence of major depressive disorder (clinical depression), generalized anxiety, stress, and depression was found to be 22.9%, 13.3%, 78.8%, and 31.6% respectively. It was also found that mental health complications are more prevalent among infertile women in Asia (continent). Considering the prevalence of mental disorders among infertile women, health policymakers can use the results of the present meta-analysis to pay more attention to the mental health of infertile women and devise suitable interventions and programs to reduce and prevent the spread of psychological disorders among infertile women.
Infertility Distress · Anxiety and Depression in Infertility
Milazzo A et al., 2016·PLoS ONE·Free full text on PubMed Central
Our study examined the psychological outcomes associated with failed ART treatment outcomes in men and women. A systematic search for studies published between January 1980 and August 2015 was performed across seven electronic databases. Studies were included if they contained data on psychosocial outcomes taken pre and post ART treatment. A standardised form was used to extract data and was verified by two independent reviewers. Studies were meta-analysed to determine the association of depression and anxiety with ART treatment outcomes. Narrative synthesis identified factors to explain variations in the size and directions of effects and relationships explored within and between the studies. Both depression and anxiety increased after a ART treatment failure with an overall pooled standardised mean difference (SMD) of 0.41 (95% CI: 0.27, 0.55) for depression and 0.21 (95% CI: 0.13, 0.29) for anxiety. In contrast, depression decreased after a successful treatment, SMD of -0.24 (95% CI: -0.37,-0.11). Both depression and anxiety decreased as time passed from ART procedure. Nonetheless, these remained higher than baseline measures in the group with the failed outcome even six months after the procedure. Studies included in the narrative synthesis also confirmed an association with negative psychological outcomes in relation to marital satisfaction and general well-being following treatment failure. Linking ART failure and psychosocial outcomes may elucidate the experience of treatment subgroups, influence deliberations around recommendations for resource allocation and health policy and guide patient and clinician decision making.
Infertility Distress · Anxiety and Depression in Infertility
Boivin J et al., 2011·BMJ·Free full text on PubMed Central
To examine whether pretreatment emotional distress in women is associated with achievement of pregnancy after a cycle of assisted reproductive technology. Meta-analysis of prospective psychosocial studies. PubMed, Medline, Embase, PsycINFO, PsychNET, ISI Web of Knowledge, and ISI Web of Science were searched for articles published from 1985 to March 2010 (inclusive). We also undertook a hand search of reference lists and contacted 29 authors. Eligible studies were prospective studies reporting a test of the association between pretreatment emotional distress (anxiety or depression) and pregnancy in women undergoing a single cycle of assisted reproductive technology. Review methods Two authors independently assessed the studies for eligibility and quality (using criteria adapted from the Newcastle-Ottawa quality scale) and extracted data. Authors contributed additional data not included in original publication. Fourteen studies with 3583 infertile women undergoing a cycle of fertility treatment were included in the meta-analysis. The effect size used was the standardised mean difference (adjusted for small sample size) in pretreatment anxiety or depression (priority on anxiety where both measured) between women who achieved a pregnancy (defined as a positive pregnancy test, positive fetal heart scan, or live birth) and those who did not. Pretreatment emotional distress was not associated with treatment outcome after a cycle of assisted reproductive technology (standardised mean difference -0.04, 95% confidence interval -0.11 to 0.03 (fixed effects model); heterogeneity I2=14%, P=0.30). Subgroup analyses according to previous experience of assisted reproductive technology, composition of the not pregnant group, and timing of the emotional assessment were not significant. The effect size did not vary according to study quality, but a significant subgroup analysis on timing of the pregnancy test, a contour enhanced funnel plot, and Egger's test indicated the presence of moderate publication bias. The findings of this meta-analysis should reassure women and doctors that emotional distress caused by fertility problems or other life events co-occurring with treatment will not compromise the chance of becoming pregnant.
Infertility Distress · Anxiety and Depression in Infertility
Schliep KC et al., 2022·Hum Reprod·Free full text on PubMed Central
What is the association between perceived stress during peri-conception and early pregnancy and pregnancy loss among women who have experienced a prior pregnancy loss? Daily perceived stress above the median is associated with over a 2-fold risk of early pregnancy loss among women who have experienced a prior loss. WHAT IS KNOWN ALREADY? Women who have experienced a pregnancy loss may be more vulnerable to stress while trying to become pregnant again. While prior research has indicated a link between psychological stress and clinically confirmed miscarriages, research is lacking among a pre-conceptional cohort followed prospectively for the effects of perceived stress during early critical windows of pregnancy establishment on risk of both hCG-detected pregnancy losses and confirmed losses, while considering important time-varying confounders. STUDY DESIGN, SIZE, Secondary data analysis of the EAGeR trial (2007-2011) among women with an hCG-detected pregnancy (n = 797 women). PARTICIPANTS/MATERIALS, SETTING, Women from four US clinical centers enrolled pre-conceptionally and were followed ≤6 cycles while attempting pregnancy and, as applicable, throughout pregnancy. Perceived stress was captured via daily diaries and end-of-month questionnaires. Main outcome measures include hCG-detected and clinically recognized pregnancy losses. MAIN Among women who had an hCG-confirmed pregnancy, 188 pregnancies (23.6%) ended in loss. Women with high (>50th percentile) versus low (≤50th percentile) peri-implantation or early pregnancy weekly perceived stress had an elevated risk of experiencing any pregnancy loss (hazard ratio (HR): 1.69, 95% CI: 1.13, 2.54) or clinical loss (HR: 1.58, 95% CI: 0.96, 2.60), with higher risks observed for women experiencing an hCG-detected loss (HR: 2.16, 95% CI: 1.04, 4.46). Models accounted for women's age, BMI, employment, marital status, income, education, race, parity, prior losses, exercise and time-varying nausea/vomiting, caffeine, alcohol and smoking. LIMITATIONS, We were limited in our ability to clearly identify the mechanisms of stress on pregnancy loss due to our sole reliance on self-reported perceived stress, and the lack of biomarkers of different pathways of stress. This study provides new insight on early pregnancy perceived stress and risk of pregnancy loss, most notably hCG-detected losses, among women with a history of a prior loss. Our study is an improvement over past studies in its ability to account for time-varying early pregnancy symptoms, such as nausea/vomiting, and lifestyle factors, such as caffeine, alcohol and smoking, which are also risk factors for psychological stress and pregnancy loss. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland (Contract numbers: HHSN267200603423, HHSN267200603424, HHSN267200603426, HHSN275201300023I). Additionally, K.C.S. was supported by the National Institute on Aging of the National Institutes of Health under Award Number K01AG058781. The authors have no conflicts of interest to disclose. #NCT00467363.
Mental Health and Psychosocial Care › Infertility Distress › Anxiety and Depression in Infertility
Annalisa Inversetti, Giampaolo Perna, Gloria Lalli, N Di Simone
A Inversetti, G Perna, G Lalli
PMID 37374051 37374051 DOI 10.3390/life13061268 10.3390/life13061268 Inversetti et al. 2023, Inversetti 2023
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