Intravaginal exposure to seminal plasma after ovum pick-up does not increase live birth rates after in vitro fertilization or intracytoplasmic sperm injection treatment: a double-blind, placebo-controlled randomized trial.

OBJECTIVE: To detect whether intravaginal exposure to prepared seminal plasma led to an absolute increase in live birth rate (LBR) after in vitro fertilization (IVF) by 10% compared with placebo. It has been suggested that intravaginal deposition of seminal plasma after ovum pick-up (OPU) for IVF treatment, increases pregnancy and LBRs. DESIGN: Double-blind, placebo-controlled prospective study. An outcome assessment was made before the type of intervention was unblinded. The outcome data were analyzed according to an intention-to-treat protocol. SETTING: University Hospital. PATIENTS: Couples scheduled for an IVF treatment cycle: in total, 792 couples (393 in the seminal plasma group and 399 in the control group) were recruited over a 5-year period of inclusion in a single-center setting. INTERVENTION: On the day of OPU, the couples were randomized into groups receiving either vaginal deposition of prepared seminal plasma from the partner or saline. Both participants and the physician were blind to the grouping. MAIN OUTCOME MEASURES: The primary outcome was a live birth (LB). The secondary outcomes were a positive pregnancy test, defined as human chorionic gonadotropin identified in urine 3 weeks after OPU , and clinical pregnancy, defined as an intrauterine viable pregnancy assessed using transvaginal sonography after 5-7 weeks. RESULTS: In the index group, 35.4% had a positive pregnancy test (relative risk [RR],0.93; 95% confidence interval {CI} 0.78-1.10), 28.8% had a clinical pregnancy (RR 1.00, 95% CI 0.97-1.03), and 26.5% had a LB (RR 0.86; 95% CI 0.70-1.07), adjusted for day of transfer, female age, and number of fertilized oocytes. Corresponding rates in the control group were 37.3%, 33.6%, and 29.8%. No statistically significant differences regarding outcomes between the two intervention groups were found. CONCLUSION: Prepared seminal plasma applied in the vagina directly after OPU did not increase the rates of LB or clinical pregnancies. The importance of immunological factors to allow the implantation of an embryo is not questioned, but no improvement in the LBRs in IVF treatment by introducing the male partner's prepared seminal plasma after OPU could be found. CLINICAL TRIAL REGISTRATION NUMBER: Clinicaltrials.gov, ID NCT02716753. Registration date 17 March, 2016, first enrollment November, 2016, completed March, 2023.

Vaginal progesterone as luteal phase support in natural cycle frozen-thawed embryo transfer (ProFET): protocol for a multicentre, open-label, randomised controlled trial.

INTRODUCTION: Vaginal progesterone supplementation is frequently given to patients receiving frozen embryo transfer (FET) in the natural cycle aiming to increase the chance of pregnancy and live birth. To date, only a few studies have investigated if progesterone supplementation is beneficial in these cycles and the level of evidence for progesterone supplementation is very low. METHODS AND ANALYSIS: The ProFET trial is a multicentre, open-label, randomised controlled trial powered for this investigation, including 1800 women with regular menstrual cycles (24-35 days), aged 18-43 years planned for natural cycle-FET receiving a single blastocyst for transfer. Participants are randomised (1:1:1) to either luteal phase progesterone for 3 weeks, luteal phase progesterone for 7 weeks or no luteal phase progesterone. The participating study centres consist of 12 in vitro fertilisation-clinics in Sweden and 1 in Iceland. The primary outcome is to investigate if luteal phase support (LPS) by vaginal progesterone increases the chance of a live birth per randomised patient in a natural FET cycle compared with no LPS. ETHICS AND DISSEMINATION: The trial was approved by the Swedish Ethical Review Authority (ID 2020-06774, 2021-02822 and 2022-01502-02) and the Swedish Medical Products Agency (ID nr 5.1-2020-102613). All participants are required to provide written informed consent. The outcome of this study will be disseminated to the public through broadcasts, newspapers and presentations at scientific congresses as well as publications in international scientific journals. TRIAL REGISTRATION NUMBER: NCT04725864.

Men born small for gestational age or with low birth weight do not improve their rate of reproduction over time: a Swedish population-based study.

OBJECTIVE: To investigate whether the reduced reproductive rate among men born small for gestational age (SGA) or with low birth weight (LBW) is present after up to 44 years of follow-up. DESIGN: Population-based register study. SETTING: National registers in Sweden. PATIENT(S): All men born in Sweden between 1973 and 1993 (n = 1,045,167) followed up to 2018. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Registered fatherhood, infertility diagnoses, and fertility treatments obtained from registers up to 2018 RESULT(S): Men born SGA or with LBW have a lower chance of becoming fathers than men born with normal birth characteristics: hazard ratio (95% confidence interval) 0.91 (0.90-0.92) and 0.88 (0.86-0.90), respectively. The reduction in reproductive rate is more evident after a longer follow-up time. Men born SGA were more likely to receive a diagnosis of infertility. Sperm donation and intracytoplasmic sperm injection were more often used in men born SGA, further strengthening the hypothesis of an association between birth characteristics and male infertility. CONCLUSION(S): Men born SGA or with LBW have a lower chance of becoming fathers, but the reduction in fertility is smaller for the younger cohort. Further studies are needed to determine if this difference is maintained.

Birth characteristics in men with infertility.

RESEARCH QUESTION: Are low birth weight, prematurity, being born small for gestational age, or both, associated with a higher risk of male factor infertility in adulthood? DESIGN: Retrospective study of a clinical sample of 892 men, diagnosed with an infertility factor (male, female, combined or unexplained) together with their female partner at a University Hospital clinic in Sweden between 2005 and 2010. Data on birth weight and gestational age at birth were retrieved from the Swedish Medical Birth Register. The distribution of non-optimal birth characteristics in relation to infertility factor was described. A control group was created consisting of two men for each index man, born in Sweden in the same year as each index men, as well as a reference group consisting of all men born in Sweden the same years. RESULTS: The likelihood of having been born small for gestational age was almost fivefold higher in men with male factor infertility than in men with unexplained infertility (OR 4.84, 95% CI 1.32 to 17.80). Men with male factor infertility were more often born with non-optimal birth characteristics than the control group (14.8% versus 8.5%; P = 0.010) and the reference group (14.8% versus 11.4%; P < 0.001). Men with azoospermia were more often born with non-optimal birth characteristics, compared with men without azoospermia (21.3% versus 12.1%; P = 0.038). CONCLUSIONS: The results suggest an association between intrauterine growth restriction and male factor infertility in adulthood.

Diagnostics of DNA fragmentation in human spermatozoa: Are sperm chromatin structure analysis and sperm chromatin dispersion tests (SCD-HaloSpermG2® ) comparable?

Men affected with idiopathic infertility often display basic spermiogramme values similar to fertile individuals, questioning the diagnostic impact of the World Health Organization (WHO) thresholds used. This study explored sperm DNA fragmentation in single ejaculates from 14 fertile donors and 42 patients with idiopathic infertility providing semen for assisted reproductive techniques in a university fertility clinic. Each ejaculate was simultaneously studied for sperm DNA fragmentation by the flow cytometer-based sperm chromatin structure analysis (SCSA) and the new light-microscopy-based sperm chromatin dispersion assay (SCD-HaloSpermG2® ), before and after sperm selection for in vitro fertilisation with a colloid discontinuous gradient. The WHO semen variables did not differ between groups, but DNA fragmentation after SCSA (DFI) or SCD (SDF) was significantly (p < 0.05) higher in patients (DFI: 40.2% ± 3.0 vs. SDF: 40.3% ± 1.4) than in fertile donors (DFI: 17.1% ± 2.1 vs. SDF: 20.9% ± 2.5). Sperm selection led to lower proportions of DNA-fragmented spermatozoa (DFI: 11.9 ± 1.7 vs. SCD: 10.0 ± 0.9, p < 0.05). The techniques output correlated highly and significantly (r2  = 0.82). DNA fragmentation is confirmed as a relevant variable for scrutinising patients with idiopathic infertility, beyond the evidently insufficient WHO semen analyses. Since both techniques yielded similar results, the reduced necessity of complex equipment when running SCD ought to be considered for a clinical setting.

Men becoming fathers by intracytoplasmic sperm injection were more often born small for gestational age.

Being born with nonoptimal birth characteristics decreases the chance of becoming a father. Urogenital malformations as well as metabolic syndrome are more common in men born small for gestational age (SGA) and could be contributing factors to the reduced fertility rate seen in these men. It could imply that men becoming fathers by assisted reproductive technology (ART) more often are born with low birth weight (LBW), preterm, and/or SGA than men conceiving without treatment and also that men where intracytoplasmic sperm injection (ICSI) had to be performed more often are born with nonoptimal birth characteristics than men where conventional in vitro fertilization (IVF) successfully could be used. In this retrospective, case-control study using Swedish national registers, we compared the birth characteristics of 1206 men who have become fathers by ART with a control group consisting of age-matched men who became fathers without treatment. The differences in birth characteristics between men becoming fathers by IVF and ICSI were also assessed. For men becoming fathers by ART, OR of being born with LBW was 1.66 (95% CI = 1.17-2.36) compared with fathers who conceived without treatment. OR of being born prematurely was 1.32 (95% CI = 1.00-1.77). Men becoming fathers via ICSI had a doubled increased likelihood of being born SGA compared with men who became fathers via IVF (OR = 2.12; 95% CI = 1.17-3.83). In conclusion, we have found that men becoming fathers by ICSI treatments had more often been born SGA than men becoming fathers by conventional IVF.

Attitudes towards the menopause and hormone therapy over the turn of the century.

OBJECTIVE: To assess attitudes and beliefs about the menopausal transition in a population of peri- and postmenopausal women, and if these attitudes differed before and after publication of studies on risks and benefits with hormone therapy (HT). MATERIALS AND METHODS: In 1999 and 2003 all women aged 53 and 54 years in the community of Linköping, Sweden, were sent a questionnaire about use of HT, menopausal status and attitudes regarding menopause and HT. RESULTS: Most women regarded menopause as a natural process characterized by both hormonal deficiency and aging and these views did not differ between 1999 and 2003. A majority of women thought that significant climacteric symptoms were a good reason to use HT, but not that women without symptoms should use HT. The fraction of women who supported HT use was, however, significantly lower in 2003 than in 1999. Most women agreed that menopause leads to increased freedom and that it is a relief not to have to think about contraception and pregnancies. CONCLUSIONS: Most Swedish women had a mainly biological view on menopause but nevertheless they thought that only women with climacteric symptoms should use HT. Women's attitudes towards HT have changed after recent reports on risks from long-term use of HT whereas the attitudes towards the menopausal transition were stable. Other factors than attitudes towards menopause affect women's actual use of HT. Probably women's and health care provider's apprehension of the risk-benefit balance of HT use is one such factor.