Declining global fertility rates and the implications for family planning and family building: an IFFS consensus document based on a narrative review of the literature.

BACKGROUND: Family-planning policies have focused on contraceptive approaches to avoid unintended pregnancies, postpone, or terminate pregnancies and mitigate population growth. These policies have contributed to significantly slowing world population growth. Presently, half the countries worldwide exhibit a fertility rate below replacement level. Not including the effects of migration, many countries are predicted to have a population decline of >50% from 2017 to 2100, causing demographic changes with profound societal implications. Policies that optimize chances to have a child when desired increase fertility rates and are gaining interest as a family-building method. Increasingly, countries have implemented child-friendly policies (mainly financial incentives in addition to public funding of fertility treatment in a limited number of countries) to mitigate decreasing national populations. However, the extent of public spending on child benefits varies greatly from country to country. To our knowledge, this International Federation of Fertility Societies (IFFS) consensus document represents the first attempt to describe major disparities in access to fertility care in the context of the global trend of decreasing growth in the world population, based on a narrative review of the existing literature. OBJECTIVE AND RATIONALE: The concept of family building, the process by which individuals or couples create or expand their families, has been largely ignored in family-planning paradigms. Family building encompasses various methods and options for individuals or couples who wish to have children. It can involve biological means, such as natural conception, as well as ART, surrogacy, adoption, and foster care. Family-building acknowledges the diverse ways in which individuals or couples can create their desired family and reflects the understanding that there is no one-size-fits-all approach to building a family. Developing education programs for young adults to increase family-building awareness and prevent infertility is urgently needed. Recommendations are provided and important knowledge gaps identified to provide professionals, the public, and policymakers with a comprehensive understanding of the role of child-friendly policies. SEARCH METHODS: A narrative review of the existing literature was performed by invited global leaders who themselves significantly contributed to this research field. Each section of the review was prepared by two to three experts, each of whom searched the published literature (PubMed) for peer reviewed full papers and reviews. Sections were discussed monthly by all authors and quarterly by the review board. The final document was prepared following discussions among all team members during a hybrid invitational meeting where full consensus was reached. OUTCOMES: Major advances in fertility care have dramatically improved family-building opportunities since the 1990s. Although up to 10% of all children are born as a result of fertility care in some wealthy countries, there is great variation in access to care. The high cost to patients of infertility treatment renders it unaffordable for most. Preliminary studies point to the increasing contribution of fertility care to the global population and the associated economic benefits for society. WIDER IMPLICATIONS: Fertility care has rarely been discussed in the context of a rapid decrease in world population growth. Soon, most countries will have an average number of children per woman far below the replacement level. While this may have a beneficial impact on the environment, underpopulation is of great concern in many countries. Although governments have implemented child-friendly policies, distinct discrepancies in access to fertility care remain.

Trabecular bone density in middle-aged women with reproductive disorders.

Besides age, estrogen exposure plays a crucial role in changes in bone density (BD) in women. Premature ovarian insufficiency (POI) and polycystic ovary syndrome (PCOS) are conditions in reproductive-aged women in which the exposure to estrogen is substantially different. Women with a history of preeclampsia (PE) are expected to have normal estrogen exposure. Within the CREw-IMAGO study, we investigated if trabecular BD is different in these women because of differences in the duration of estrogen exposure. Trabecular BD was measured in thoracic vertebrae on coronary CT scans. Women with an reduced estrogen exposure (POI) have a lower BD compared to women with an intermediate exposure (PE) (mean difference (MD) -26.8, 95% confidence interval (CI) -37.2 - -16.3). Women with a prolonged estrogen exposure (PCOS) have the highest BD (MD 15.0, 95% CI 4.3 - 25.7). These results support the hypothesis that the duration of estrogen exposure in these women is associated with trabecular BD.

Change in Androgenic Status and Cardiometabolic Profile of Middle-Aged Women with Polycystic Ovary Syndrome.

Understanding the cardiovascular disease (CVD) risk for women with polycystic ovary syndrome (PCOS) at reproductive age is crucial. To investigate this, we compared the cardiometabolic profiles of different PCOS groups over a median interval of 15.8 years. The study focused on three groups: (1) women with PCOS who were hyperandrogenic at both initial and follow-up screening (HA-HA), (2) those who transitioned from hyperandrogenic to normoandrogenic (HA-NA), and (3) those who remained normoandrogenic (NA-NA). At initial and follow-up screenings, both HA-HA and HA-NA groups showed higher body mass indexes compared to the NA-NA group. Additionally, at follow-up, the HA-HA and HA-NA groups exhibited higher blood pressure, a higher prevalence of hypertension, elevated serum triglycerides and insulin levels, and lower levels of HDL cholesterol compared to the NA-NA group. Even after adjusting for BMI, significant differences persisted in HDL cholesterol levels and hypertension prevalence among the groups (HA-HA: 53.8%, HA-NA: 53.1%, NA-NA: 14.3%, p < 0.01). However, calcium scores and the prevalence of coronary plaques on CT scans were similar across all groups. In conclusion, women with PCOS and hyperandrogenism during their reproductive years exhibited an unfavorable cardiometabolic profile during their post-reproductive years, even if they changed to a normoandrogenic status.

Decreased role of neuropeptides in the microvascular function in migraine patients with polycystic ovary syndrome.

BACKGROUND AND AIMS: To understand pathophysiological mechanisms underlying migraine as a cardiovascular risk factor, we studied neuropeptide action and endothelial function as measures of peripheral microvascular function in middle-aged women with or without migraine. METHODS: We included women with the endocrine disorder polycystic ovary syndrome (PCOS), a population with supposed elevated cardiovascular risk, with and without comorbid migraine. In 26 women without and 23 women with migraine in the interictal phase (mean age 50.8 ± 2.9 years) local thermal hyperemia (LTH) of the skin of the volar forearm was measured cross-sectionally under control conditions, after inhibition of neuropeptide release by 5% lidocaine/prilocaine (EMLA) cream application, and after inhibition of nitric oxide formation by iontophoresis of NG-monomethyl-l-arginine (L-NMMA). Hereafter, changes in the natural logarithm of the reactive hyperemia index (lnRHI) and augmentation index (AI) during reperfusion after occlusion-derived ischemia were measured. RESULTS: While mean values under control conditions and L-NMMA conditions were similar, migraine patients had a significantly higher mean area of the curve (AUC) of the total LTH response after EMLA application than those without (86.7 ± 26.5% versus 67.9 ± 24.2%; p = 0.014). This was also reflected by a higher median AUC of the plateau phase under similar conditions in women with migraine compared to those without (83.2% (IQR[73.2-109.5]) versus 73.2% (IQR[54.3-92.0]); p = 0.039). Mean changes in lnRHI and AI scores were similar in both groups. CONCLUSIONS: In PCOS patients with migraine, neuropeptide action was lower compared with those without migraine. While larger studies are warranted, these findings provide a potential mechanism supporting previous findings that migraine may be independent from traditional risk factors, including atherosclerosis.

Predicting pregnancy chances leading to term live birth in oligo/anovulatory women diagnosed with PCOS.

RESEARCH QUESTION: Which patient features predict the time to pregnancy (TTP) leading to term live birth in infertile women diagnosed with polycystic ovary syndrome (PCOS)? DESIGN: Prospective cohort follow-up study was completed, in which initial standardized phenotyping was conducted at two Dutch university medical centres from January 2004 to January 2014. Data were linked to the Netherlands Perinatal Registry to obtain pregnancy outcomes for each participant. All women underwent treatment according to a standardized protocol, starting with ovulation induction as first-line treatment. Predictors of pregnancies (leading to term live births) during the first year after PCOS diagnosis were evaluated. RESULTS: A total of 1779 consecutive women diagnosed with PCOS between January 2004 and January 2014 were included. In the first year following screening, 659 (37%) women with PCOS attained a pregnancy leading to term birth (≥37 weeks of gestational age). A higher chance of pregnancy was associated with race, smoking, body mass index (BMI), insulin, total testosterone and sex hormone-binding globulin (SHBG) concentrations (c-statistic = 0.59). CONCLUSIONS: Predictors of an increased chance of a live birth include White race, no current smoking, lower BMI, insulin and total testosterone concentrations, and higher SHBG concentrations. This study presents a nomogram to predict the chances of achieving a pregnancy (leading to a term live birth) within 1 year of treatment.

Incidental findings on coronary computed tomography in women with selected reproductive disorders.

OBJECTIVE: To determine the prevalence of incidental findings (IFs) on coronary computed tomography (CCT) in women aged 45-55 years and previously diagnosed with reproductive disorders such as polycystic ovary syndrome (PCOS), premature ovarian insufficiency (POI) or preeclampsia (PE). METHODS: A total of 486 middle-aged women with PCOS (n = 101), POI (n = 97) or a history of PE (n = 288) underwent a CCT as part of a prior prospective study. IFs were categorized by their significance (minor, moderate and major). Follow-up information was collected from patients' records. To investigate the impact of different field of views (FOVs), a subset of scans was analyzed in full FOV and small FOV. RESULTS: In 96/486 (19.8%) women, one or more IFs were detected, of which 54/486 (11.1%) were classified as moderate/major and 48/486 (9.9%) required follow-up. A moderate/major IF was detected in 16/101 (15.9%) women with PCOS, 13/97 (13.4%) women with POI and 25/288 (8.7%) women with a history of PE. In 78 women with an IF detected in the full FOV, the IF was still visible in 60 (76.9%) women in the small FOV. In the full FOV, 46 women required follow-up, but using the small FOV this was reduced to 30 women. CONCLUSION: Using CCT as a cardiovascular disease screening tool in women with selected reproductive disorders increases the probability of detecting IFs that can cause anxiety and may generate extra costs, but can also reveal clinically relevant findings. Using a small FOV centered around the heart resulted in a lower prevalence of IFs and required less follow-up.

Randomized Controlled Trial of Neurokinin 3 Receptor Antagonist Fezolinetant for Treatment of Polycystic Ovary Syndrome.

CONTEXT: Polycystic ovary syndrome (PCOS), a highly prevalent endocrine disorder characterized by hyperandrogenism, is the leading cause of anovulatory infertility. OBJECTIVE: This proof-of-concept study evaluated clinical efficacy and safety of the neurokinin 3 (NK3) receptor antagonist fezolinetant in PCOS. METHODS: This was a phase 2a, randomized, double-blind, placebo-controlled, multicenter study (EudraCT 2014-004409-34). The study was conducted at 5 European clinical centers. Women with PCOS participated in the study. Interventions included fezolinetant 60 or 180 mg/day or placebo for 12 weeks. The primary efficacy end point was change in total testosterone. Gonadotropins, ovarian hormones, safety and tolerability were also assessed. RESULTS: Seventy-three women were randomly assigned, and 64 participants completed the study. Adjusted mean (SE) changes in total testosterone from baseline to week 12 for fezolinetant 180 and 60 mg/day were -0.80 (0.13) and -0.39 (0.12) nmol/L vs -0.05 (0.10) nmol/L with placebo (P < .001 and P < .05, respectively). Adjusted mean (SE) changes from baseline in luteinizing hormone (LH) for fezolinetant 180 and 60 mg/d were -10.17 (1.28) and -8.21 (1.18) vs -3.16 (1.04) IU/L with placebo (P < .001 and P = .002); corresponding changes in follicle-stimulating hormone (FSH) were -1.46 (0.32) and -0.92 (0.30) vs -0.57 (0.26) IU/L (P = .03 and P = .38), underpinning a dose-dependent decrease in the LH-to-FSH ratio vs placebo (P < .001). Circulating levels of progesterone and estradiol did not change significantly vs placebo (P > .10). Fezolinetant was well tolerated. CONCLUSION: Fezolinetant had a sustained effect to suppress hyperandrogenism and reduce the LH-to-FSH ratio in women with PCOS.

Early Onset of Coronary Artery Calcification in Women With Previous Preeclampsia.

BACKGROUND: Preeclampsia, coronary artery calcification (CAC), and atherosclerotic plaque are risk factors for the development of cardiovascular disease. We determined at what age CAC becomes apparent on coronary computed tomography after preeclampsia and to what extent modifiable cardiovascular risk factors were associated. METHODS: We measured cardiovascular risk factors, CAC by coronary computed tomography, and coronary plaque by coronary computed tomography angiography in 258 previously preeclamptic women aged 40-63. Results were compared to 644 age- and ethnicity-equivalent women from the Framingham Heart Study with previous normotensive pregnancies. RESULTS: Any CAC was more prevalent after preeclampsia than after a normotensive pregnancy (20% versus 13%). However, this difference was greatest and statistically significant only in women ages 45 to 50 (23% versus 10%). The degree of CAC advanced 4× faster between the ages of 40 to 45 and ages 45 to 50 in women with a history of preeclampsia (odds ratio, 4.3 [95% CI, 1.5-12.2] versus odds ratio, 1.2 [95% CI, 0.6-2.3]). Women with a preeclampsia history maintained greater advancement of CAC with age into their early 60s, although this difference declined after the perimenopausal years. Women with a previous normotensive pregnancy were 4.9 years (95% CI, 1.8-8.0) older when they had similar CAC scores as previously preeclamptic women. These observations were not explained by the greater prevalence of cardiovascular disease risk factors, and the higher Framingham Risk Scores also observed in women with a history of preeclampsia. CONCLUSIONS: Previously preeclamptic women have more modifiable cardiovascular risk factors and develop CAC ≈5 years earlier from the age of 45 years onwards compared to women with normotensive pregnancies. Therefore, women who experienced preeclampsia might benefit from regular cardiovascular screening and intervention before this age. Registration: URL: https://www.trialregister.nl/trial/5406; Unique identifier: NTR5531.

Does an association exist between menstrual cycle length within the normal range and ovarian reserve biomarkers during the reproductive years? A systematic review and meta-analysis.

BACKGROUND: Regular menstrual cycling during the reproductive years is an indicator of spontaneous ovulation but sometimes falsely perceived as an indicator of preserved fertility. In contrast, menstrual cycle shortening, a physiologic occurrence preceding the menopausal transition, is not usually perceived as an indicator of decreased ovarian reserve in the general population. OBJECTIVE AND RATIONALE: The individual decrease in menstrual cycle length (MCL) might represent a sensitive biomarker of diminishing ovarian reserve. The aim of this systematic review and meta-analysis is to examine the possible association between MCL in regularly cycling women (21-35 days) and ovarian reserve tests (ORT), fecundability in natural cycles and IVF outcomes. SEARCH METHODS: An electronic database search employing PubMed, Web of Science, Trip, EBSCO, ClinicalTrials.gov and the Cochrane library was performed to identify research articles, only on human, published between January 1978 and August 2019. Search terms were pregnancy OR fertility OR fecundity OR fecundability, anti-Müllerian hormone OR AMH OR antral follicle count OR AFC OR ovarian reserve OR ovarian reserve test, in vitro fertilization OR ART OR assisted reproductive therapy OR assisted reproductive treatment OR assisted reproductive technology OR IVF OR ICSI, menstrual cycle length OR menstrual cycle characteristics. We combined these terms to complete the search. All prospective and retrospective studies exploring an association between MCL and proxies of ovarian reserve were included. The exclusions included studies of PCOS, ovarian failure, oral contraception treatment, prior chemotherapy and/or radiotherapy or ovarian surgery. The Newcastle-Ottawa scale was used to assess the quality of studies that were eligible for meta-analysis. OUTCOMES: Eleven studies were eligible for meta-analysis, including 12 031 women. The included studies had a low risk of bias. Short MCL (21-27 days) was associated with lower ORT values as compared to normal (28-31 days), long (32-35 days) and all other (28-35 days) MCL sets. The estimated weighted mean difference (WMD) of AMH level was -1.3 ng/mL (95% CI: -1.75 to -0.86, P < 0.001) between the short and normal MCL sets. The estimated WMD of AFC values was -5.17 (95% CI: -5.96 to -4.37, P < 0.001) between the short and normal MCL sets. The weighted overall odds ratio (OR) of fecundability in natural cycles between women with short versus normal MCL sets was statistically significant (overall OR 0.81; 95% CI 0.72-0.91, P < 0.001). In the IVF setting, fewer oocytes were retrieved in short MCL in comparison to normal, long and all other MCL sets, with an estimated WMD of -1.8 oocytes (95% CI: -2.5 to -1.1, P < 0.001) in the short versus normal MCL sets. The weighted overall OR of clinical pregnancy rate between women with short versus all other MCL sets was statistically significant (overall OR 0.76; 95% CI: 0.60 to 0.96, P = 0.02). Low levels of heterogeneity were found in most meta-analyses of MCL and qualitative ovarian reserve biomarkers, while heterogeneity was high in meta-analyses performed for quantitative measures. WIDER IMPLICATIONS: MCL in regularly cycling women is closely related to ovarian reserve biomarkers during the reproductive years. A short MCL, as compared to normal, is significantly associated with lower ORT values, reduced fecundability and inferior IVF outcomes, independent of age. The results imply that short MCL may be a sign of ovarian aging, combining the quantitative and qualitative facets of ovarian reserve. Educational efforts ought to be designed to guide women with short MCL at a young age, who desire children in the future, to seek professional counselling.

The cardiovascular risk profile of middle age women previously diagnosed with premature ovarian insufficiency: A case-control study.

BACKGROUND: Cardiovascular disease (CVD) is the leading cause of death in women worldwide. The cardiovascular risk profile deteriorates after women enter menopause. By definition, women diagnosed with premature ovarian insufficiency (POI) experience menopause before 40 years of age, which may render these women even more susceptible to develop CVD later in life. However, prospective long-term follow up data of well phenotyped women with POI are scarce. In the current study we compare the CVD profile and risk of middle aged women previously diagnosed with POI, to a population based reference group matched for age and BMI. METHODS AND FINDINGS: We compared 123 women (age 49.0 (± 4.3) years) and diagnosed with POI 8.1 (IQR: 6.8-9.6) years earlier, with 123 population controls (age 49.4 (± 3.9) years). All women underwent an extensive standardized cardiovascular screening. We assessed CVD risk factors including waist circumference, BMI, blood pressure, lipid profile, pulse wave velocity (PWV), and the prevalence of diabetes mellitus, metabolic syndrome (MetS) and carotid intima media thickness (cIMT), in both women with POI and controls. We calculated the 10-year CVD Framingham Risk Score (FRS) and the American Heart Association's suggested cardiovascular health score (CHS). Waist circumference (90.0 (IQR: 83.0-98.0) versus 80.7 (IQR: 75.1-86.8), p < 0.01), waist-to-hip ratio (0.90 (IQR: 0.85-0.93) versus 0.79 (IQR: 0.75-0.83), p < 0.01), systolic blood pressure (124 (IQR 112-135) versus 120 (IQR109-131), p < 0.04) and diastolic blood pressure (81 (IQR: 76-89) versus 78 (IQR: 71-86), p < 0.01), prevalence of hypertension (45 (37%) versus 21 (17%), p < 0.01) and MetS (19 (16%) versus 4 (3%), p < 0.01) were all significantly increased in women with POI compared to healthy controls. Other risk factors, however, such as lipids, glucose levels and prevalence of diabetes were similar comparing women with POI versus controls. The arterial stiffness assessed by PWV was also similar in both populations (8.1 (IQR: 7.1-9.4) versus 7.9 (IQR: 7.1-8.4), p = 0.21). In addition, cIMT was lower in women with POI compared to controls (550 µm (500-615) versus 684 µm (618-737), p < 0.01). The calculated 10-year CVD risk was 5.9% (IQR: 3.7-10.6) versus 6.0% (IQR: 3.9-9.0) (p = 0.31) and current CHS was 6.1 (1.9) versus 6.5 (1.6) (p = 0.07), respectively in POI versus controls. CONCLUSIONS: Middle age women with POI presented with more unfavorable cardiovascular risk factors (increased waist circumference and a higher prevalence of hypertension and MetS) compared to age and BMI matched population controls. In contrast, the current study reveals a lower cIMT and similar 10-year cardiovascular disease risk and cardiovascular health score. In summary, neither signs of premature atherosclerosis nor a worse cardiovascular disease risk or health score were observed among middle age women with POI compared to population controls. Longer-term follow-up studies of women of more advanced age are warranted to establish whether women with POI are truly at increased risk of developing CVD events later in life. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02616510.

Circulating Neutrophils Do Not Predict Subclinical Coronary Artery Disease in Women with Former Preeclampsia.

: Introduction: Preeclampsia (PE) represents a hypertensive pregnancy disorder that is associated with increased cardiovascular disease (CVD) risk. This increased risk has been attributed to accelerated atherosclerosis, with inflammation being a major contributor. Neutrophils play an important role in the onset and progression of atherosclerosis and have been associated with vascular damage in the placenta as well as the chronic inflammatory state in women with PE. We therefore investigated whether circulating neutrophil numbers or reactivity were associated with the presence and severity of subclinical atherosclerosis in women with a history of PE. METHODS: Women aged 45-60 years with a 10 to 20 years earlier history of early onset preeclampsia (delivery <34 weeks of gestation) (n = 90), but without symptomatic CVD burden were screened for the presence of subclinical coronary artery disease (CAD) using both contrast-enhanced and non-contrast coronary CT angiography. Subclinical CAD was defined as a coronary artery calcium (CAC) score ≥100 Agatston Units and/or ≥50% coronary luminal stenosis. We assessed whether the numbers and activity of circulating neutrophils were associated with the presence of subclinical CAD and as secondary outcome measurements, with the presence of any calcium (CAC score > 0 AU) or stenosis, categorized as absent (0%), minimal to mild (>0 and <50%), and moderate to severe (≥50%) narrowing of the coronary artery. Blood was drawn just before CT and neutrophil numbers were assessed by flow cytometry. In addition, the presence of the chemokine receptors CXCR2 and CXCR4, which are known to be instrumental in neutrophil recruitment, and neutrophil activity upon stimulation with the bacterial peptide N-Formylmethionyl-leucyl-phenylalanine (fMLF) was assessed by flow cytometry. RESULTS: Of the participating women, with an average age of 49 years, 13% (12 out of 90) presented with subclinical signs of CAD (CAC score ≥100 AU and/or ≥50% luminal stenosis), and 37% (33 out of 90) had a positive CAC score (>0). Total white blood cell count and neutrophil counts were not associated with the presence of subclinical CAD or with a positive CAC score. When assessing the presence of the chemokine receptors CXCR4 and CXCR2, we observed a slight decrease of neutrophil CXCR2 expression in women with CAC (median MFI 22.0 [interquartile range (IQR) 20.2-23.8]) compared to women without CAC (23.8 [IQR 21.6-25.6], p = 0.02). We observed no differences regarding neutrophil CXCR4 expression. In addition, expression of the early activity marker CD35 was slightly lower on neutrophils of women with subclinical CAD (median MFI 1.6 [IQR 1.5-1.9] compared to 1.9 [IQR 1.7-2.1] in women without CAD, p = 0.02). However, for all findings, statistical significance disappeared after adjustment for multiple testing. CONCLUSION: Our findings indicate that neutrophil counts and (re)activity are not directly associated with silent CAD disease burden and as such are not suitable as biomarkers to predict the presence of subclinical CAD in a high-risk population of women with a history of preeclampsia.

Cardiometabolic health in offspring of women with PCOS compared to healthy controls: a systematic review and individual participant data meta-analysis.

BACKGROUND: Women diagnosed with polycystic ovary syndrome (PCOS) suffer from an unfavorable cardiometabolic risk profile, which is already established by child-bearing age. OBJECTIVE AND RATIONALE: The aim of this systematic review along with an individual participant data meta-analysis is to evaluate whether cardiometabolic features in the offspring (females and males aged 1-18 years) of women with PCOS (OPCOS) are less favorable compared to the offspring of healthy controls. SEARCH METHODS: PubMed, Embase and gray literature databases were searched by three authors independently (M.N.G., M.A.W and J.C.) (last updated on 1 February 2018). Relevant key terms such as 'offspring' and 'PCOS' were combined. Outcomes were age-specific standardized scores of various cardiometabolic parameters: BMI, blood pressure, glucose, insulin, lipid profile and the sum scores of various cardiometabolic features (metabolic sum score). Linear mixed models were used for analyses with standardized beta (ß) as outcome. OUTCOMES: Nine relevant observational studies could be identified, which jointly included 1367 children: OPCOS and controls, originating from the Netherlands, Chile and the USA. After excluding neonates, duplicate records and follow-up screenings, a total of 885 subjects remained. In adjusted analyses, we observed that OPCOS (n = 298) exhibited increased plasma levels of fasting insulin (ß = 0.21(95%CI: 0.01-0.41), P = 0.05), insulin-resistance (ß = 0.21(95%CI: 0.01-0.42), P = 0.04), triglycerides (ß = 0.19(95%CI: 0.02-0.36), P = 0.03) and high-density lipoprotein (HDL)-cholesterol concentrations (ß = 0.31(95%CI: 0.08-0.54), P < 0.01), but a reduced birthweight (ß = -116(95%CI: -195 to 38), P < 0.01) compared to controls (n = 587). After correction for multiple testing, however, differences in insulin and triglycerides lost their statistical significance. Interaction tests for sex revealed differences between males and females when comparing OPCOS versus controls. A higher 2-hour fasting insulin was observed among female OPCOS versus female controls (estimated difference for females (ßf) = 0.45(95%CI: 0.07 to 0.83)) compared to the estimated difference between males ((ßm) = -0.20(95%CI: -0.58 to 0.19)), with interaction-test: P = 0.03. Low-density lipoprotein-cholesterol differences in OPCOS versus controls were lower among females (ßf = -0.39(95%CI: -0.62 to 0.16)), but comparable between male OPCOS and male controls (ßm = 0.27(95%CI: -0.03 to 0.57)), with interaction-test: P < 0.01. Total cholesterol differences in OPCOS versus controls were also lower in females compared to the difference in male OPCOS and male controls (ßf = -0.31(95%CI: -0.57 to 0.06), ßm = 0.28(95%CI: -0.01 to 0.56), interaction-test: P = 0.01). The difference in HDL-cholesterol among female OPCOS versus controls (ßf = 0.53(95%CI: 0.18-0.88)) was larger compared to the estimated mean difference among OPCOS males and the male controls (ßm = 0.13(95%CI: -0.05-0.31), interaction-test: P < 0.01). Interaction test in metabolic sum score revealed a significant difference between females (OPCOS versus controls) and males (OPCOS versus controls); however, sub analyses performed in both sexes separately did not reveal a difference among females (OPCOS versus controls: ßf = -0.14(95%CI: -1.05 to 0.77)) or males (OPCOS versus controls: ßm = 0.85(95%CI: -0.10 to 1.79)), with P-value < 0.01. WIDER IMPLICATIONS: We observed subtle signs of altered cardiometabolic health in OPCOS. Therefore, the unfavorable cardiovascular profile of women with PCOS at childbearing age may-next to a genetic predisposition-influence the health of their offspring. Sensitivity analyses revealed that these differences were predominantly observed among female offspring aged between 1 and 18 years. Moreover, studies with minimal risk of bias should elucidate the influence of a PCOS diagnosis in mothers on both sexes during fetal development and subsequently during childhood.