Ovulation induction and subfertile untreated conception groups offer improved options for interpreting risks associated with ART.

PURPOSE: To identify and characterise appropriate comparison groups for population studies of health outcomes in ART-conceived births: ovulation induction (OI), subfertile untreated and fertile natural conceptions. Our secondary objective was to examine whether known risks of pregnancy complications and adverse birth outcomes in ART births are elevated in comparison with subfertile (untreated and OI) conception groups. METHODS: We linked State and Commonwealth datasets to identify all live and stillbirths (≥ 20 weeks) in Western Australia from 2003 to 2014 by method of conception. Demographic characteristics, maternal pre-existing conditions, adverse obstetric history and pregnancy complications were compared across conception groups. Generalised estimating equations were used to estimate adjusted risk ratios (aRRs) and 95% confidence intervals (CI) for pregnancy complications and birth outcomes in singletons. RESULTS: We identified 9456 ART, 3870 OI, 11,484 subfertile untreated and 303,921 fertile naturally conceived deliveries. OI and subfertile untreated groups more closely resembled the ART group than the fertile group; however, some differences remained across parity, maternal age, pre-existing conditions and obstetric history. In multivariate analyses, ART singletons had greater risks of placental problems (e.g. placenta praevia aRR 2.42 (95% CI 1.82-3.20)) and adverse birth outcomes (e.g. preterm birth aRR 1.38 (95% CI 1.25-1.52)) than the subfertile untreated group, while OI singletons were more similar to the subfertile group with higher risk of preeclampsia and gestational diabetes. CONCLUSION: OI and subfertile untreated conception groups offer improved options for interpreting health outcomes in ART births. Pregnancy complications (particularly placental disorders) and adverse outcomes at delivery are more common following ART.

Asthma and allergies in a cohort of adolescents conceived with ART.

RESEARCH QUESTION: Are asthma and allergies more common in adolescents conceived with assisted reproductive technologies (ART) compared with adolescents conceived without? DESIGN: The Growing Up Healthy Study (GUHS) is a prospective cohort study including ART-conceived offspring born between 1991 and 2001 in Perth, Australia. Their long-term health outcomes, including asthma and allergy parameters, were compared with those of their counterparts conceived without ART from the Raine Study Generation 2 (Gen2), born in 1989-1991. At age 14, 152 GUHS and 1845 Gen2 participants completed the following assessments: the International Studies of Asthma and Allergies in Childhood (ISAAC) questionnaire, spirometry, methacholine challenge testing and skin prick testing (SPT). RESULTS: No differences were detected in the prevalence of current asthma (7.7% versus 10.8%, adjusted odds ratio [aOR] 0.82 (95% CI 0.44-1.52), P = 0.530). Spirometry-measured lung volumes were larger in the ART adolescents. Bronchial hyperresponsiveness was less prevalent in the ART cohort (8.8 versus 18.6%, P = 0.006). Current allergic rhinoconjunctivitis (ARC) rates were significantly higher in the ART cohort (32.4% versus 25.2%, aOR 1.52 [95% CI 1.03-2.26], P = 0.036), with no cohort differences in atopic dermatitis. Food allergies were more prevalent in the ART cohort (20.7 versus 10.9%, aOR 1.89 [95% CI 1.17-3.06], P = 0.010) with more adolescents having a positive SPT (68.0% versus 45.4%, aOR 3.03 [95% 1.99-4.63], P < 0.001). CONCLUSIONS: This study reports no differences in asthma prevalence, slightly altered lung function, an increase in ARC, food allergies and positive SPT in the ART-conceived adolescents. These findings are important to families and healthcare providers and may open up possibilities for targeted screening and treatment. Further studies are required to confirm these findings.

Pathogenesis of endometriosis: Look no further than John Sampson.

Rather than consider endometriosis as an enigmatic disease, reading John Sampson's two theories/mechanisms explains virtually all cases affecting the female. It is true that Sampson's most recent publication, in 1940, which talks about retrograde menstruation via the fallopian tubes, clearly fails to explain many types of endometriosis, particularly that located in extra-pelvic sites. However, his earlier publications of 1911 and 1912, on radiographic studies of hysterectomy specimens that had been injected with various gelatin/bismuth/pigment mixtures examining the unique uterine vasculature, were more important. These studies enabled him to describe 'the escape of foreign material from the uterine cavity into the uterine veins' in 1918 and subsequently to demonstrate metastatic or embolic endometriosis in the first of his two important publications in 1927. Later in that same year, in response to 'academic banter' from other historic gynaecologists, he published a second article that indicated his studies had been redirected to explore the retrograde tubal menstruation idea; this required undertaking his hysterectomies during menses. That work led to his 1940 presentation at the invitation of The American College of Obstetricians and Gynecologists to focus on the second theory/mechanism of endometriosis. This appears to have caused his more important first theory/mechanism to have been forgotten.

Serum Vitamin D status is associated with increased blastocyst development rate in women undergoing IVF.

RESEARCH QUESTION: To determine the relationship between vitamin D (VitD) status and embryological, clinical pregnancy and live birth outcomes in women undergoing IVF. DESIGN: Cross-sectional, observational study conducted at a university-affiliated private IVF clinic. A total of 287 women underwent 287 IVF cycles and received a fresh embryo transfer. Patients had their serum 25-hydroxyvitamin D2/D3 (VitD) determined on the day of oocyte retrieval, which was analysed in relation to blastocyst development rate, clinical pregnancy and live birth outcomes. RESULTS: In stepwise, multivariable logistic regression models, increases in blastocyst development rate, number and quality, along with embryo cryopreservation and utilization rates were associated with women with a sufficient VitD status (≥20 ng/ml). For a single increase in the number of blastocysts generated per cycle or embryos cryopreserved per cycle, the likelihood for the patient to be VitD sufficient was increased by 32% (odds ratio [OR] 1.32, 95% confidence interval [CI] 1.10-1.58, P = 0.002 and OR 1.33, 95% CI 1.10-1.60, P = 0.004, respectively). Clinical pregnancy (40.7% versus 30.8%, P = 0.086) and live birth rates (32.9% versus 25.8%, P = 0.195) in the sufficient VitD group versus the insufficient group were not significantly different and VitD sufficiency was not significantly associated with these outcomes. CONCLUSION: A strong relationship was observed between blastocyst development and VitD sufficiency. However, there was no association between VitD and clinical pregnancy or live birth outcomes. Further larger studies are needed to investigate whether the observed effect on blastocyst development may have downstream implications on subsequent clinical pregnancy or live birth rates, and on a potential mechanism where sufficient VitD concentrations are linked to improved IVF outcomes.

Advanced fibroid study: paying homage to John Sampson.

A recent article supports our longstanding view that all intramural fibroids can cause disturbance of uterine function. This may be reflected in the symptom of menorrhagia or fertility-related issues, as well as pregnancy losses at all gestational stages. However, it was disappointing that there was no reference to either the mechanism by which fibroids disturb uterine function nor to the gynaecologist who described this more than 100 years ago, namely John Sampson. In fact, Sampson's findings about the unique venous drainage mechanism from the endometrium explains how menstrual loss is contained in normal physiology, but which can be excessive when the protective 'anaemic' zone is disturbed. Two more recent and pertinent observations include the hysteroscopic findings of Osamu Sugimoto, who showed in the 1970s that the endometrium overlying submucous fibroids is actually atrophic, hence the oft-cited reason of hyperplastic or excessive endometrium cannot be the cause of the associated menorrhagia. Furthermore, recent imaging techniques describe an additional 'junctional zone' adjacent to the endometrium in cases of fibroids and adenomyosis. We believe this all adds up to disturbed venous drainage as described by Sampson and needs to immediately enter the educational training of medical students, doctors and gynaecologists worldwide.

Finding a place for corifollitropin within the PIVET FSH dosing algorithms.

PIVET recombinant FSH (rFSH) dosing algorithms have been designed for rFSH injection pens, providing optimal pregnancy and live birth productivity rates whilst minimizing risk and occurrence of ovarian hyperstimulation syndrome (OHSS). Recently, long-acting recombinant gonadotrophin corifollitropin (Elonva) was approved for use in assisted reproduction, and welcomed by patients as the single injection allowed ovarian stimulation over 7 days without need for multiple injections. Consequently, another rFSH dosing algorithm was devised to incorporate Elonva, and these cycles were compared to standard rFSH agents, Gonal-f and Puregon. Initiated Elonva cycles (n = 165) were compared with 972 cycles initiated with standard rFSH. Elonva replaced standard rFSH dosages across the 200-400 IU range, but provided equivalent oocyte retrieval numbers and live birth outcomes. Elonva is considered risky for women whose antral follicle count is ≥20 follicles, and was inadvertently administered contra-protocol in 19 cycles with ≥20 follicles. However, while oocyte retrieval numbers were higher, raising risk for OHSS, no actual cases ensued. Taken together, this indicated that Elonva was equivalent to standard rFSH stimulation, and consequently has been added to the rFSH algorithms for medium to lower antral follicle counts and represented by green colour coding in the existing PIVET algorithmic charts.

Molecular actions of vitamin D in reproductive cell biology

Vitamin D (VitD) is an important secosteroid and has attracted attention in several areas of research due to common VitD deficiency in the population, and its potential to regulate molecular pathways related to chronic and inflammatory diseases. VitD metabolites and the VitD receptor (VDR) influence many tissues including those of the reproductive system. VDR expression has been demonstrated in various cell types of the male reproductive tract, including spermatozoa and germ cells, and in female reproductive tissues including the ovaries, placenta and endometrium. However, the molecular role of VitD signalling and metabolism in reproductive function have not been fully established. Consequently, the aim of this work is to review current metabolic and molecular aspects of the VitD­VDR axis in reproductive medicine and to propose the direction of future research. Specifically, the influence of VitD on sperm motility, calcium handling, capacitation, acrosin reaction and lipid metabolism is examined. In addition, we will also discuss the effect of VitD on sex hormone secretion and receptor expression in primary granulosa cells, along with the impact on cytokine production in trophoblast cells. The review concludes with a discussion of the recent developments in VitD­VDR signalling specifically related to altered cellular bioenergetics, which is an emerging concept in the field of reproductive medicine.

Higher ß-HCG concentrations and higher birthweights ensue from single vitrified embryo transfers.

To examine the effect of cryopreservation on developmental potential of human embryos, this study compared quantitative ß-HCG concentrations at pregnancy test after IVF-fresh embryo transfer (IVF-ET) with those arising after frozen embryo transfer (FET). It also tracked outcomes of singleton pregnancies resulting from single-embryo transfers that resulted in singleton live births (n = 869; with 417 derived from IVF-ET and 452 from FET). The initial serum ß-HCG concentration indicating successful implantation was measured along with the birthweight of the ensuing infants. With testing at equivalent luteal phase lengths, the median pregnancy test ß-HCG was significantly higher following FET compared with fresh IVF-ET (844.5 IU/l versus 369 IU/l; P < 0.001). Despite no significant difference in the average period of gestation (38 weeks 5 days for both groups), the mean birthweight of infants born following FET was significantly heavier by 161 g (3370 g versus 3209 g; P < 0.001). Furthermore, more infants exceeded 4000 g (P < 0.001) for FET although there was no significant difference for the macrosomic category (≥4500 g). We concluded that FET programme embryos lead to infants with equivalent (if not better) developmental potential compared with IVF-ET, demonstrated by higher pregnancy ß-HCG concentrations and ensuing birthweights.

The effect of cigarette smoking, alcohol consumption and fruit and vegetable consumption on IVF outcomes: a review and presentation of original data.

BACKGROUND: Lifestyle factors including cigarette smoking, alcohol consumption and nutritional habits impact on health, wellness, and the risk of chronic diseases. In the areas of in-vitro fertilization (IVF) and pregnancy, lifestyle factors influence oocyte production, fertilization rates, pregnancy and pregnancy loss, while chronic, low-grade oxidative stress may underlie poor outcomes for some IVF cases. METHODS: Here, we review the current literature and present some original, previously unpublished data, obtained from couples attending the PIVET Medical Centre in Western Australia. RESULTS: During the study, 80 % of females and 70 % of male partners completed a 1-week diary documenting their smoking, alcohol and fruit and vegetable intake. The subsequent clinical outcomes of their IVF treatment such as quantity of oocytes collected, fertilization rates, pregnancy and pregnancy loss were submitted to multiple regression analysis, in order to investigate the relationship between patients, treatment and the recorded lifestyle factors. Of significance, it was found that male smoking caused an increased risk of pregnancy loss (p = 0.029), while female smoking caused an adverse effect on ovarian reserve. Both alcohol consumption (ß = 0.074, p < 0.001) and fruit and vegetable consumption (ß = 0.034, p < 0.001) had positive effects on fertilization. CONCLUSION: Based on our results and the current literature, there is an important impact of lifestyle factors on IVF clinical outcomes. Currently, there are conflicting results regarding other lifestyle factors such as nutritional habits and alcohol consumption, but it is apparent that chronic oxidative stress induced by lifestyle factors and poor nutritional habits associate with a lower rate of IVF success.

Mid-luteal serum progesterone concentrations govern implantation rates for cryopreserved embryo transfers conducted under hormone replacement.

This study explores the relevance of mid-luteal serum hormonal concentrations in cryopreserved embryo transfer cycles conducted under hormone replacement therapy (HRT) control and which involved single-embryo transfer (SET) of 529 vitrified blastocysts. Widely ranging mid-luteal oestradiol and progesterone concentrations ensued from the unique HRT regimen. Oestradiol had no influence on clinical pregnancy or live birth rates, but an optimal progesterone range between 70 and 99 nmol/l (P < 0.005) was identified in this study. Concentrations of progesterone below 50 nmol/l and above 99 nmol/l were associated with decreased implantation rates. There was no clear interaction between oestradiol and progesterone concentrations but embryo quality grading did show a significant influence on outcomes (P < 0.001 and P = 0.002 for clinical pregnancy and live birth rates, respectively). Multiple comparison analysis showed that the progesterone effect was influential regardless of embryo grading, body mass index or the woman's age, either at vitrification or at cryopreserved embryo transfer. The results support the argument that careful monitoring of serum progesterone concentrations in HRT-cryopreserved embryo transfer is warranted and that further studies should explore pessary adjustments to optimize concentrations for individual women to enhance implantation rates.

Follicle recruitment determines IVF productivity rate via the number of embryos frozen and subsequent transfers.

IVF productivity rate is an index defined as the sum of all live births from either fresh or frozen embryo transfers arising from a single oocyte collection. This retrospective analysis over 9 continuous years used this index to understand the potential impact on pregnancy rates of milder stimulation regimens with associated reduced egg numbers. The productivity rate per collection increased in a linear and significant rate as more oocytes were recovered, more embryos frozen and more frozen embryo transfers contributed to pregnancy. This observation was true for women aged <35 years and less so for women aged 35-39 years but not for women aged 40 years and older. The contribution of frozen embryo transfer to the productivity rate rose in a linear manner, reaching over 40% of all live births with nine oocytes. The number of live births per oocyte, pronuclear embryos and thawed embryos decreased significantly but the number of live births per embryo transferred (fresh or frozen) rose with rising oocyte numbers, reflecting increasing opportunity for embryo selection. This study suggests that optimal benefits with minimal risks are gained from a model that includes both fresh and frozen transfers under stimulation generating between 8 and 12 eggs.

Cohort profile: The Growing Up Healthy Study (GUHS)-A prospective and observational cohort study investigating the long-term health outcomes of offspring conceived after assisted reproductive technologies.

Worldwide, over 8 million children and adults are conceived following assisted reproductive technologies (ART), and their long-term health is of consequential public health interest. The objective of this paper is to describe the Growing up Healthy Study (GUHS) cohort in detail, publicise it and invite collaboration. Combining the data collected in the GUHS with other cohorts or databases will improve the much-needed knowledge about the effects of ART, and allow for better understanding of the long-term health outcomes of offspring conceived after ART. The GUHS cohort is a prospective observational study of adolescents and young adults conceived after assisted reproductive technologies (ART). It was established to determine if the long-term health of offspring conceived by ART differs from that of the general population. This was investigated by comparing a substantial number of health parameters to those of a representative population of offspring conceived without ART. The n = 303 GUHS participants were born between 1991-2001 in the two fertility clinics operating at the time in Perth, Western Australia, and undertook assessments at ages 14, 17 and 20, replicating the pre-defined study protocols from the reference cohort-the Raine Study. Participants were comprehensively phenotyped through detailed questionnaires, anthropometry, biochemical analyses, as well as age-specific assessments (asthma, atopy, cardiometabolic health, body composition, mental health, thyroid function, epigenetics and vision). To date the GUHS cohort has been used to study the methylation, cardiometabolic, and thyroid profiles, as well as respiratory and mental health. To summarise, the GUHS cohort provides a valuable addition to the limited knowledge of the long-term health outcomes of ART-conceived offspring.

Invited commentary: the politics of human embryo research and the motivation to achieve PGD.

The idea that biomedical research can be influenced by political events implies a teleological basis indicating that scientific achievements occur because there is a political need. Such a concept appears to have been the reason PGD was fast-tracked to emerge as a biomedical achievement well before its due date, occurring at a time when human embryology was still struggling to reach a reasonable level of efficiency and become adopted as a clinically relevant advance around the world. One story underlying the historical achievement of the HFE Act 1990, enabling regulated embryo research, steps outside the firm ground of biomedical science and encourages the idea that Reproductive BioMedicine Online should embrace a further section enabling articles dealing with 'History, politics and personalities' where these influence biomedical research.

SARS-CoV-2 pandemic and repercussions for male infertility patients: A proposal for the individualized provision of andrological services.

The prolonged lockdown of health facilities providing non-urgent gamete cryopreservation-as currently recommended by many reproductive medicine entities and regulatory authorities due to the SARS-CoV-2 pandemic will be detrimental for subgroups of male infertility patients. We believe the existing recommendations should be promptly modified and propose that the same permissive approach for sperm banking granted for men with cancer is expanded to other groups of vulnerable patients. These groups include infertility patients (eg, azoospermic and cryptozoospermic) undergoing medical or surgical treatment to improve sperm quantity and quality, as well as males of reproductive age affected by inflammatory and systemic auto-immune diseases who are about to start treatment with gonadotoxic drugs or who are under remission. In both scenarios, the "fertility window" may be transitory; postponing diagnostic semen analysis and sperm banking in these men could compromise the prospects of biological parenthood. Moreover, we provide recommendations on how to continue the provision of andrological services in a considered manner and a safe environment. Our opinion is timely and relevant given the fact that fertility services are currently rated as of low priority in most countries.

Growth hormone supplementation improves implantation and pregnancy productivity rates for poor-prognosis patients undertaking IVF.

In a sequential crossover study of IVF conducted from 2002 to 2006, growth hormone (GH) supplementation was assessed in poor-prognosis patients, categorized on the basis of past failure to conceive (mean 3.05 cycles) due to low response to high-dose stimulation (<3 metaphase II oocytes) or poor-quality embryos. Pregnancy rates in both fresh and frozen transfer cycles and the total productivity rates (fresh and frozen pregnancies per egg collection) were compared. In all, 159 patients had 488 treatment cycles: 221 with GH and 241 without GH. These cycles were also compared with 1572 uncategorized cycles from the same period. GH co-treatment significantly improved the clinical pregnancy rate per fresh transfer (P<0.001) as well as per frozen-thawed embryo derived from GH cycles (P<0.05) creating a highly significant productivity rate (P<0.001). The effect was significant across all age groups, especially in younger patients, and was independent of stimulation modality or number of transfers. GH cycles resulted in significantly more babies delivered per transfer than non-GH cycles (20% versus 7%; P<0.001) although less than the uncategorized cycles (53%). The data uniquely show that the effect of GH is directed at oocyte and subsequent embryo quality.