Risk of colorectal cancer after use of fertility drugs-results from a large Danish population-based cohort of women with infertility.

OBJECTIVE: To study the association between use of fertility drugs and colorectal cancer among women with infertility. DESIGN: Population-based cohort study. SETTING: Not applicable. PATIENT(S): The study cohort was obtained from the Danish Infertility Cohort and consisted of all women with infertility aged 20-45 years living in Denmark during 1995-2017. INTERVENTION(S): Information on the use of specific types of fertility drugs, colorectal cancer diagnoses, covariates, and vital status were obtained from the Danish Infertility Cohort and Danish national registers. MAIN OUTCOME MEASURE(S): Cox proportional hazard models adjusted for potential confounders were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for colorectal cancer overall and rectal and colon cancer separately. RESULTS(S): Among 148,036 women in the final study cohort, 205 women were diagnosed with colorectal cancer. Ever use of clomiphene citrate (CC) was associated with a lower rate of colorectal cancer (unadjusted HR, 0.67; 95% CI, 0.51-0.89; adjusted HR, 0.68; 95% CI, 0.50-0.93). However, the lower rate was only seen among women who first used CC >8 years ago (unadjusted HR, 0.56; 95% CI, 0.41-0.76; adjusted HR, 0.52; 95% CI, 0.36-0.75). No marked associations were found between the use of any of other types of fertility drugs and colorectal cancer. The results for colon and rectal cancer analyzed separately were similar, except for a suggestion of a decreased risk of rectal cancer associated with the use of gonadotropins (adjusted HR, 0.46; 95% CI, 0.20-1.08). CONCLUSION(S): Among women with infertility, the use of most types of fertility drugs was not associated with colorectal cancer. However, CC may decrease the risk of colorectal cancer and gonadotropins might decrease the risk of rectal cancer, but we cannot rule out that these findings may be more related to the underlying conditions in these women or are chance findings. Consequently, the results from this study should be investigated further in large epidemiological studies.

Fertility drugs and incidence of thyroid cancer in a Danish nationwide cohort of 146 024 infertile women.

STUDY QUESTION: Do fertility drugs increase the risk of thyroid cancer among infertile women? SUMMARY ANSWER: The use of most types of fertility drugs was not associated with an increased risk of thyroid cancer. WHAT IS KNOWN ALREADY: The incidence of thyroid cancer is higher for women than men, especially during reproductive years, indicating that reproductive hormones may be involved in the development of thyroid cancer. Only a few previous studies have examined the association between the use of fertility drugs and incidence of thyroid cancer and the results are inconclusive. STUDY DESIGN, SIZE, DURATION: A retrospective, population-based cohort study including all 146 024 infertile women aged 20-45 years and living in Denmark in the period 1995-2017. The women were followed from the date of entry in the cohort (i.e. date of first infertility diagnosis) until the occurrence of thyroid cancer or any other cancer (except non-melanoma skin cancer), death, emigration, total thyroidectomy or the end of follow-up (31 December 2018), whichever occurred first. The median length of follow-up was 11.3 years. PARTICIPANTS/MATERIALS, SETTING, METHODS: In total, 167 women were diagnosed with thyroid cancer during the follow-up period. Information on the use of specific fertility drugs (clomiphene citrate, gonadotropins, hCGs, GnRH receptor modulators and progesterone), thyroid cancer, covariates and vital status was obtained from the Danish Infertility Cohort and various Danish national registers. Cox proportional hazard regression models were used to calculate hazard ratios (HRs) and 95% CIs for thyroid cancer overall and for papillary thyroid cancer. MAIN RESULTS AND THE ROLE OF CHANCE: After adjustment for the calendar year of infertility diagnosis, the highest obtained level of education, parity status, obesity or thyroid disease and mutual adjustment for other registered fertility drugs, no marked associations were observed between the use of clomiphene citrate, hCG, gonadotropins or GnRH receptor modulators and risk of overall or papillary thyroid cancer. However, ever use of progesterone was associated with an increased rate of both overall (HR 1.63; 95% CI 1.07-2.48) and papillary (HR 1.66, 95% CI 1.04-2.65) thyroid cancer after mutual adjustment for other specific fertility drugs. For most specific fertility drugs, we observed a tendency toward higher associations with thyroid cancer within the first 5 years after the start of drug use than after 5 years from the start of use. No marked associations were detected according to the cumulative dose for any of the specific fertility drugs. LIMITATIONS, REASONS FOR CAUTION: Despite a large study population, the statistical precision in some subgroup analyses may be affected due to the low number of thyroid cancer cases. Although we were able to adjust for a number of potential confounders, residual and unmeasured confounding may potentially have affected the observed associations, as we could not adjust for some factors that may influence the association between fertility drugs and thyroid cancer, including age at menarche and BMI. WIDER IMPLICATIONS OF THE FINDINGS: Although this study, which is the largest to date, provides reassuring evidence that there is no strong link between the use of fertility drugs and thyroid cancer incidence, we observed a modest increased thyroid cancer incidence after the use of progesterone. However, we cannot rule out that this is a chance finding and the potential association between the use of progesterone and thyroid cancer should therefore be investigated further in large epidemiological studies. The results of the present study provide valuable knowledge for clinicians and other health care personnel involved in the diagnosis and treatment of infertility. STUDY FUNDING/COMPETING INTEREST(S): The study was supported by research grants from the Jascha Foundation and the Aase and Ejner Danielsens Foundation. B.N. received honoraria and/or non-financial support by Gedeon Richter Nordics AB, IBSA Nordic APS and Merck KGAA. The remaining authors have no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Use of Fertility Drugs and Risk of Malignant Melanoma: Results from a Large Danish Population-Based Cohort Study.

Fertility drugs have not definitively been linked to malignant melanoma. By the use of data from a large nationwide cohort of women aged 20.0-45.0 years and living in Denmark between January 1, 1995 and December 31, 2011, we assessed the association between the use of fertility drugs and the risk of malignant melanoma. Information on fertility status and the use of fertility drugs was obtained from the population-based Danish Infertility Cohort. Cox proportional hazard regression models were applied to estimate hazard ratios and 95% confidence intervals with adjustment for potential confounders. The study population comprised 1,330,954 women, of whom 86,231 (6.5%) were treated with fertility drugs. During a median follow-up of 21.0 years, 6,139 women were diagnosed with malignant melanoma. Compared with fertile women, women with fertility challenges who had used any fertility drugs had an increased risk of malignant melanoma (hazard ratio = 1.14; 95% confidence interval = 1.02-1.27). Furthermore, the use of specific types of fertility drugs (clomiphene, gonadotropins, human chorionic gonadotropin, gonadotropin-releasing hormone preparations, and progesterone) was also associated with an increased risk of malignant melanoma, with hazard ratios ranging between 1.09 and 1.13; however, the association did not reach statistical significance. Our findings indicate that the use of fertility drugs was associated with a modestly increased risk of malignant melanoma.

The association between fertility treatments and the incidence of paediatric cancer: A systematic review and meta-analysis.

BACKGROUND: It is important to explore the association between different fertility treatments and the incidence of paediatric cancer, as this will provide crucial guidance for clinical decision-making. Previous studies have explored the relationship between fertility treatments and different types of cancer in offspring, but the results are controversial. METHOD: Two authors searched PubMed, Embase, Web of Science and Cochrane databases independently to acquire qualified studies. Then, the same authors extracted data from these studies and analysed these data using RevMan 5.3. MAIN RESULTS: Eleven case-control studies and 16 cohort studies were included in this review and meta-analysis. The relative risk of association between in vitro fertilisation (IVF) and paediatric cancer incidence was 1.01 (95% confidence interval [CI]: 0.80-1.28) in cohort studies and 1.09 (95% CI: 0.74-1.58) in case-control studies. The relative risk of association between intracytoplasmic sperm injection (ICSI) and paediatric cancer incidence was 0.97 (95% CI: 0.80-1.17) in cohort studies. The relative risk of association between fertility drugs and paediatric cancer incidence was 1.07 (95% CI: 0.68-1.69) in cohort studies and 1.12 (95% CI: 0.90-1.41) in case-control studies. The relative risk of association between frozen embryo transfer and paediatric cancer incidence was 1.37 (95% CI: 1.04-1.81) in natural pregnancy controls and 1.28 (95% CI: 0.96-1.69) in fresh embryo transfer controls. CONCLUSION: There is no evidence that IVF, ICSI and fertility drugs are associated with an increase in paediatric cancer incidence in offspring; however, frozen embryo transfer is associated with an increase in paediatric cancer incidence in the offspring, but this finding needs further research and attention.

Pregnancy registry: three-year follow-up of children conceived from letrozole, clomiphene, or gonadotropins.

OBJECTIVE: To study the development of children conceived from non-IVF infertility treatments consisting of gonadotropins, clomiphene, or letrozole. DESIGN: Prospective cohort study. SETTING: U.S. academic health centers. PATIENT(S): Children of women with polycystic ovary syndrome who conceived with letrozole (LTZ) or clomiphene (CC) in the PPCOS II study or women with unexplained infertility (AMIGOS study) who conceived with LTZ, CC, or gonadotropin (GN). INTERVENTION(S): Longitudinal annual follow-up from birth to age 3. MAIN OUTCOME MEASURE(S): Scores from Ages and Stages Developmental Questionnaire (ASQ), MacArthur-Bates Communicative Development Inventory (MCDI), and annual growth. RESULT(S): One hundred eighty-five children from 160 families participated in at least one follow-up evaluation from the two infertility trials. Most multiple gestations in the follow-up study resulted from GN treatment (n = 14) followed by CC (n = 6) and LTZ (n = 3). There were no significant differences among the three groups at any time point with respect to abnormal scores on the ASQ. On the MCDI Words and Gestures, the LTZ group scored significantly higher than the GN group for most items (phrases, early gestures, later gestures, and total gestures). Children in the CC group scored significantly higher than the GN group for the later gestures and total gestures items. CONCLUSION(S): Differences in growth and cognitive developmental rates among children conceived with first-line infertility therapies, including LTZ, are relatively minor and likely due to differences in multiple pregnancy rates.

Endometrial compaction before frozen euploid embryo transfer improves ongoing pregnancy rates.

OBJECTIVE: To assess whether the calculated difference in endometrial thickness from the end of the estrogen phase to the day of ET (after 6 days of P in hormonally prepared cycles) is associated with ongoing pregnancy rates in euploid frozen ETs (FETs). DESIGN: An observational cohort study. SETTING: Single tertiary care medical center. PATIENT(S): Ultrasound images from 234 hormonally prepared FET cycles were assessed. All the transfers were elective single ETs of a euploid embryo, post-preimplantation genetic testing for aneuploidy (PGT-A). INTERVENTION(S): Ultrasound measurements of peak endometrial thickness at the end of the estrogen phase and again after 6 days of P at the time of ET. MAIN OUTCOME MEASURE(S): Ongoing pregnancy rate in relation to the delta between endometrial thickness at the end of estrogen phase and at the time of ET. RESULT(S): We calculated the ongoing pregnancy rate in cycles where the endometrial lining decreased (compacted) after addition of P by 5%, 10%, 15%, and 20% and demonstrated a significantly higher pregnancy rate after all rates of compaction of the endometrial lining in comparison with cycles where the endometrial lining did not compact. The ongoing pregnancy rate in this cohort, after compaction of 15% or more, was 51.5%, compared with 30.2% in cycles where the endometrial lining did not compact. CONCLUSION(S): There is a significant correlation between endometrial lining compaction and ongoing pregnancy rate in FET cycles of euploid embryos. These findings help to explain why some euploid embryos may fail to implant.

Fertility drugs and cutaneous melanoma risk: a French prospective cohort study.

Cutaneous melanoma has been suspected to be influenced by female sex hormones. A review of the literature in 2018 indicated that fertility drug (FD) use was associated with increased melanoma risk among parous women only. However, most studies so far were based on a retrospective design and the current evidence is unclear. We sought to prospectively investigate the associations between FD use and melanoma risk in women. E3N is a prospective cohort of 98 995 French women aged 40-65 years at inclusion in 1990. Information on use of FDs, including duration and time of administration, was assessed through self-administered questionnaires. We used Cox proportional hazards regression models adjusted for age and melanoma risk factors. Over 1990-2008, about 611 melanoma cases were ascertained among 86 653 women. Compared with never use, ever use of FDs was not associated with melanoma risk overall [hazard ratio (HR) = 1.15; 95% confidence interval (CI) = 0.75-1.74], or among parous women (HR = 1.08; 95% CI = 0.67-1.73). Among ever users of FDs, duration of use and age at first use were not associated with melanoma risk. Associations were similar after adjustment for UV exposure, although FD users were more likely to report tanning bed use than never-users (odds ratio = 1.50; CI = 1.01-2.22) in a subsample with recreational UV exposure data. Our data do not support an association between FD use and melanoma risk, but underlie the importance of taking into consideration potential confounding from sun exposure in future research.

In vitro fertilization add-ons for the endometrium: it doesn't add-up.

The probability of live birth from an in vitro fertilization (IVF) cycle is modest. Many additional treatments (add-ons) are available which promise to improve the success of IVF. This review summarizes the current evidence for common IVF add-ons which are suggested to improve endometrial receptivity. Systematic reviews of randomized controlled trials and individual trials were included. Five add-ons were included: immune therapies, endometrial scratching, endometrial receptivity array, uterine artery vasodilation, and human chorionic gonadotropin instillation. The results suggest there is no robust evidence that these add-ons are effective or safe. Many IVF add-ons are costly, consuming precious resources which may be better spent on evidence-based treatments or further IVF. Large randomized controlled trials and appropriate safety assessment should be mandatory before the introduction of IVF add-ons into routine practice.

Clinical adjuncts in in vitro fertilization: a growing list.

A growing list of clinical adjuncts are being used during in vitro fertilization (IVF) treatment. Most of these IVF add-ons (such as growth hormone, aspirin, heparin, dehydroepiandrostenedione, testosterone, male and female antioxidants, and screening hysteroscopy) are being introduced into routine clinical practice in a hurried manner without any clear evidence of benefit in most cases. These add-ons make the IVF more complicated and increase the overall cost for the treatment, which is borne by the couples and health care providers. Our current review found no high-quality evidence to support the use of these IVF add-ons in routine practice. Large, well-designed, randomized trials must be conducted to evaluate the effectiveness and safety of these interventions. There is also a pressing need to develop an evidence-dictated mechanism for introducing newer interventions into routine clinical settings.

A Cohort Study of Breast Cancer Risk after 20 Years of Follow-Up of Women Treated with Fertility Drugs.

BACKGROUND: Using a nationwide cohort of Danish women, we investigated the association between use of fertility drugs and risk of breast cancer. METHODS: The study cohort included women ages 20 to 44 years and living in Denmark between January 1, 1995 and December 31, 2011. Information on fertility status, use of fertility drugs, breast cancer, covariates, and vital status was obtained from the Danish Infertility Cohort and various Danish national registers. Cox proportional hazard regression models were applied to estimate hazard ratios (HR) and 95% confidence intervals (CI), adjusted for potential confounders. RESULTS: Of the 1,330,852 women included, 96,782 (7.3%) were infertile, and 20,567 (1.5%) were diagnosed with breast cancer during a median follow-up of 20.9 years. Compared with fertile women, infertile women who had used any fertility drugs did not have an increased hazard for breast cancer overall (HR = 1.02; 95% CI, 0.95-1.10), or for any of the histologic types (ductal, lobular, or mucinous) of breast cancer. Furthermore, no associations were observed between use of specific types of fertility drugs and breast cancer. CONCLUSIONS: No convincing associations between use of fertility drugs and breast cancer were observed after two decades of follow-up. IMPACT: Our results do not support a marked association between fertility drugs and breast cancer and are therefore reassuring for infertile women treated with fertility drugs.

Risk of juvenile idiopathic arthritis among children conceived after fertility treatment: a nationwide registry-based cohort study.

STUDY QUESTION: Is the risk of juvenile idiopathic arthritis (JIA) increased in children conceived after fertility treatment, and is an observed association caused by specific types of fertility treatment or by factors associated with the underlying infertility? SUMMARY ANSWER: The risk of JIA in children conceived after fertility treatment (any and specific types of fertility treatment) was not convincingly affected when compared with children born to fertile women. WHAT IS KNOWN ALREADY: It has been suggested that fertility treatment may affect the development of the immune system and thereby increase the risk of developing autoimmune diseases, including JIA. STUDY DESIGN, SIZE, DURATION: This retrospective population-based cohort study included all live-born children in Denmark between 1 January 1996 and 31 December 2012 (n = 1 084 184). The study population was followed from date of birth until first diagnosis of JIA as registered in the Danish National Patient Registry, date of 16th birthday, date of emigration, date of death or end of follow-up (31 December 2014), whichever occurred first. PARTICIPANTS/MATERIALS, SETTING, METHODS: The study cohort was linked to the Danish Infertility Cohort in order to identify children born to women with fertility problems (n = 174 702) and fertility treatment (n = 89 931). Cox proportional hazard regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) adjusted for potential confounders. MAIN RESULTS AND THE ROLE OF CHANCE: During a median follow-up period of 10.3 years, 2237 children were diagnosed with JIA. Children born to women with fertility problems had an increased risk of JIA (HR 1.18, 95% CI 1.05-1.32) compared with children born to fertile women. However, the risk was not increased in children conceived after any fertility treatment (HR 1.11; 95% CI 0.95-1.29), or after specific types of fertility treatment being ART (HR 1.05; 95% CI 0.83-1.33), IVF (HR 1.01; 95% CI 0.73-1.38), ICSI (HR 0.98; 95% CI 0.64-1.50) or any fertility drugs (HR 1.10; 95% CI 0.94-1.28) compared with children born to fertile women. The associations between fertility treatment and JIA were also assessed by using children born to women with fertility problems without fertility treatment in the index pregnancy as a reference group, however, the findings did not change substantially. LIMITATIONS REASONS FOR CAUTION: Despite a large study population, the statistical precision in some subgroup analyses may be affected due to the low number of JIA cases. There may be some misclassification of fertility problems, as some women have undiagnosed fertility problems and are therefore not included in the Danish Infertility Cohort; potentially leading to slight attenuation of the association between fertility problems and JIA. WIDER IMPLICATIONS OF THE FINDINGS: The results are based on national data and our findings can therefore be applied to other similar populations. Our results indicate that fertility treatment per se do not increase the risk of JIA but merely that the increased risk of JIA observed among children born to women with fertility problems may be due to underlying factors related to both infertility and JIA. However, as this is the first large study in this field, further studies are needed to confirm our findings. STUDY FUNDING/COMPETING INTEREST(S): The study was supported by grants from the Jascha Foundation, the Aase and Ejner Danielsens Foundation and The Danish Rheumatism Association. All authors report no conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.

Thyroid cancer risk in women with infertility and association with fertility medications in Taiwan.

BACKGROUND: The current study evaluated whether the risk of developing thyroid cancer in Asian women was associated with infertility and the use of fertility drugs. METHODS: The authors conducted a large, retrospective cohort study using Taiwan's National Health Insurance Research Database. From the insurance claims data, a total of 13,356 women aged 20 to 49 years who were diagnosed with infertility from 2000 through 2013 were included in the infertile group, and 53,424 women without a history of infertility were selected as fertile comparisons and were frequency matched by age and year of diagnosis. Both groups were followed up to 2013 to calculate incident thyroid cancer. Poisson regression analysis was used to estimate the incidence rate ratio (IRR). RESULTS: The incidence of thyroid cancer was 1.9-fold greater in the infertile group compared with the comparison group (2.85 vs 1.53 per 10,000 person-years), with an adjusted IRR of 1.80 (95% confidence interval [95% CI], 1.70-1.92) for the infertile group. Higher cancer incidence was demonstrated for the infertile group after 7 years of follow-up, with an adjusted IRR of 4.39 (95% CI, 4.03-4.78) compared with the comparison group. Among infertile women, those who had taken the fertility drug clomiphene were found to have a reduced incidence of thyroid cancer compared with those who were treated without the drug (2.69 vs 3.42 per 10,000 person-years), with an adjusted IRR of 0.86 (95% CI, 0.75-0.99). However, the cancer incidence in infertile women being treated with clomiphene was nearly 6-fold greater than that in fertile women taking the drug. CONCLUSIONS: The results of the current study provide evidence that women with infertility are at an increased risk of developing thyroid cancer.

Benefits of Empiric Nutritional and Medical Therapy for Semen Parameters and Pregnancy and Live Birth Rates in Couples with Idiopathic Infertility: A Systematic Review and Meta-analysis.

CONTEXT: Empiric use of medical and nutritional supplements to improve semen parameters and pregnancy rates in couples with idiopathic infertility has reached global proportions, although the evidence base for their use in this setting is controversial. OBJECTIVE: We systematically reviewed evidence comparing the benefits of nutritional and medical therapy on pregnancy rates and semen parameters in men with idiopathic infertility. EVIDENCE ACQUISITION: A literature search was performed using MEDLINE, Embase, LILACS, and the Cochrane Library (searched from January 1, 1990 to September 19, 2017). using the methods detailed in the Cochrane Handbook. Grading of Recommendations Assessment, Development and Evaluation (GRADE) was used to assess the certainty of evidence. EVIDENCE SYNTHESIS: The literature search identified 5663 citations, and after screening of abstracts and full texts, 61 studies (59 randomised controlled trials and two nonrandomised comparative studies) were included. Pooled results demonstrated that pentoxyfylline, coenzyme Q10, L-carnitine, follicle-stimulating hormone, tamoxifen, and kallikrein all resulted in improvements in semen parameters. Individual studies identified several other medical and nutritional therapies that improved semen parameters, but data were limited to individual studies with inherent methodological flaws. There were limited data available on live birth and pregnancy rates for all interventions. The GRADE certainty of evidence for all outcomes was very low mainly owing to methodological flaws and inconsistencies in study design. Some outcomes were also downgraded owing to imprecision of results. CONCLUSIONS: There is some evidence that empiric medical and nutritional supplements may improve semen parameters. There is very limited evidence that empiric therapy leads to better live birth rates, spontaneous pregnancy, or pregnancy following assisted-reproductive techniques. However, the findings should be interpreted with caution as there were some methodological flaws, as a number of studies were judged to be either at high or unclear risk of bias for many domains. PATIENT SUMMARY: This review identified several medical and nutritional treatments, such as pentoxyfylline, coenzyme Q10, L-carnitine, follicle-stimulating hormone, tamoxifen, and kallikrein, that appear to improve semen parameters. However, there are limited data suggesting improvements in pregnancy and live birth rates. The lack of evidence can be attributed to methodological flaws in studies and the low number of pregnancies reported.

Associations of hormonal contraceptives and infertility medications on the risk of venous thromboembolism, ischemic stroke, and cardiovascular disease in women.

The purpose of this study was to examine the relations of hormonal contraceptives and infertility drugs with the risk of venous thromboembolism (VTE), deep vein thrombosis (DVT), pulmonary embolism (PE), ischemic stroke, and cardiovascular disease. The Taiwan National Health Institute Research Database was searched for women who had taken hormonal contraceptives or infertility medications from 2000 to 2010. The two groups were age and index date matched with controls (1:4 ratios). Cox regression analysis was used to examine the risks of VTE, DTE, PE, ischemic stroke, and cardiovascular disease. A total of 32,067 women were included in the hormonal contraceptives group and 4710 in the infertility medications group (matched controls: 127,872 and 18,840, respectively). After adjustment for age, comorbidities, and other confounders, the contraceptives group had a higher risk of VTE (adjusted HR 1.14, 95% CI 1.004 to 1.30) and cardiovascular disease (adjusted HR 1.30, 95% CI 1.26 to 1.34), and lower risk of ischemic stroke (adjusted HR 0.90, 95% CI 0.86 to 0.95). The infertility medications group had a higher risk of VTE (adjusted HR 1.996, 95% CI 1.41 to 2.72) and DVT (adjusted HR 1.86, 95% CI 1.31 to 2.63), and lower risk of ischemic stroke (adjusted HR 0.82, 95% CI 0.68 to 0.99) and cardiovascular disease (adjusted HR 0.83, 95% CI 0.74 to 0.94). Hormonal contraceptives and infertility medications appear to lower the risk of ischemic stroke and increase the risk of VTE; however, their effect on the risk of other types of cardiovascular events varies.

Impact of antioxidant treatment on DNA fragmentation index: a double-blind placebo-controlled randomized trial.

BACKGROUND: Previous reports on effect of antioxidants on sperm DNA integrity were equivocal, and there is a lack of randomized, placebo-controlled studies. OBJECTIVES: To evaluate the efficacy of combined antioxidant treatment in subfertile men with normal reproductive hormone levels and high sperm DNA fragmentation index (DFI). MATERIALS AND METHODS: This placebo-controlled, double-blind, randomized study evaluated the effects of combined antioxidant treatment in 77 men from infertile couples, with normal testosterone, LH and FSH levels and DFI ≥25%. All participants were randomly assigned to receive combined antioxidant treatment (vitamins, antioxidants and oligoelements) or placebo for six months. The primary outcome measured was DFI. Secondary outcomes were standard semen parameters. DFI and other semen parameters were, at each time point (pre-treatment, and after three and six months of treatment), compared between the treatment and the placebo group using Mann-Whitney U-test. RESULTS: Antioxidant group had higher sperm concentration after three months of treatment (median: 24.4 × 106 /mL vs. 27.2 × 106 /mL; P = 0.028) and borderline statistically significant higher concentration after six months of treatment (median: 24.4 × 106 /mL vs. 33.3 × 106 /mL; P = 0.053) compared to pre-treatment values. The DFI did not change during the 6 months of antioxidant therapy. No statistically significant difference between the antioxidant and placebo group was seen for any of the semen parameters including sperm DFI at any of the three time points. DISCUSSION: The increase in sperm concentration was more pronounced in the antioxidant treated group but not statistically significantly higher than among controls, perhaps due to insufficient statistical power. Previous studies have shown positive effect of antioxidant treatment on DFI and other semen parameters. However, our findings indicate that men with normal reproductive hormone levels may not be the primary target group for such therapy. CONCLUSION: Six months treatment with antioxidants had no effect on sperm DFI.

Fertility Drugs Associated with Thyroid Cancer Risk: A Systematic Review and Meta-Analysis.

Associations have been demonstrated between fertility drugs and a variety of hormone-sensitive carcinomas. The purpose of this study was to determine the relationship between fertility drugs used in the treatment of female infertility and the risk of thyroid cancer. To investigate the clinical significance of fertility drugs used for the treatment of female infertility and the risk associated with thyroid cancer, we performed a literature search using PubMed, MEDLINE, the Cochrane Library, the Web of Science, and EBSCOHOST for comparative studies published any time prior to July 21, 2017. The studies included women who were treated for infertility with fertility drugs, such as clomiphene citrate, gonadotropins, or other unspecified fertility agents, which reported the incidence of thyroid cancer as the main outcome. Eight studies were included in the meta-analyses. Among women with infertility, there was a significant positive association between thyroid cancer risk and the use of fertility drugs (relative risk [RR] = 1.35; 95% confidence interval [CI] 1.12-1.64; P = 0.002). Additionally, among women with infertility, the use of clomiphene citrate was associated with an increased risk of thyroid cancer compared to women who did not use fertility drugs (RR = 1.45; 95% CI 1.12-1.88; P = 0.005). After pooling results, we found that the parity status of infertile women using fertility drugs was not associated with thyroid cancer risk (RR = 0.99; 95% CI 0.61-1.58, P = 0.95). In summary, clomiphene citrate (the most commonly used fertility drug) and other fertility drugs are associated with an increased risk of thyroid cancer.

Infertility treatments during pregnancy and the risk of autism spectrum disorder in the offspring.

We aimed to examine the effects of infertility treatments on the risk of Autism Spectrum Disorder (ASD). Data were from a representative national registry on 110,093 male live births in Israel (born: 1999-2008; and ASD: 975, 0.9%). Infertility treatments included In Vitro Fertilization (IVF), and five hormone treatments. Relative risk (RR) was estimated with multivariable logistic models. Results showed that IVF treatment compared with spontaneous conception was not statistically significantly associated with the risk of ASD. Only progesterone hormone treatment was associated with a statistically significant (p < .05) increased risk of ASD (RR = 1.51, 95% CI 1.22, 1.86) compared to the group with no progesterone treatment. In conclusion, progesterone exposure during the critical period of fetal life elevated the risk of ASD, possibly reflecting epigenetic modification.

Utilization of the Bologna criteria: a promise unfulfilled? A review of published and unpublished/ongoing trials.

OBJECTIVE: To study the use of the Bologna criteria (BC) for the definition of poor ovarian responders (POR) in clinical practice and research. DESIGN: Systematic review of published and unpublished/ongoing trials between January 2012 and August 2017 on POR. SETTING: Not applicable. PATIENT(S): Not applicable. INTERVENTION(S): The databases were searched using the relevant medical subject headings including all subheadings. The search was limited to humans and English language. The references of the included studies were cross-searched for possibly missed articles. Only clinical trials providing an evidence level ≥ III were included. Case reports, review, letters, and hypothetical articles were excluded. MAIN OUTCOME MEASURE(S): Extracted studies were divided into two groups: studies in which the BC were used or not. RESULT(S): One hundred nine published clinical studies analyzing a total of 30,540 women and 112 unpublished/ongoing trials were identified. The BC were used to define POR in 56 (51%) of the published and 44 (39%) of the unpublished trials. The use of the BC gradually increased from 29% to 53% from 2012 to 2017. Asian researchers were more likely to use the BC compared with European and North American researchers (65%, 49%, and 23%, respectively). Neither the design of the study nor the impact factor of the publishing journal was correlated with the use of the BC. CONCLUSION(S): There is still reluctance to use the BC for the definition of POR, which makes it difficult to combine data from small studies and reach a meaningful conclusion.