Impact of female obesity and assisted reproduction on uncomplicated pregnancies and healthy births: a study of 428 336 births in Flanders.

STUDY QUESTION: What is the impact of BMI on uncomplicated pregnancies and healthy births in women who did or did not have medically assisted reproduction (MAR, i.e. ART or hormonal stimulation without manipulation of eggs or embryos) in the Flanders region (Belgium)? SUMMARY ANSWER: Women with a higher BMI who use MAR are at the highest risk of pregnancy and birth complications. WHAT WE KNOW ALREADY: Medically assisted reproduction (MAR) is used increasingly worldwide and is associated with increased risk of adverse perinatal outcomes. Obesity is also increasing globally and obese women are more likely to seek MAR since obesity is associated with infertility. When obese women undergo MAR, the risk of adverse outcomes may be enhanced but it is not clear to what extent. STUDY DESIGN, SIZE, DURATION: We conducted a registry-based study using the data from the Study Centre for Perinatal epidemiology database for years 2009-2015, region of Flanders, Belgium. This included 428 336 women. PARTICIPANTS/MATERIALS, SETTING, METHODS: The average age was 30.0 years (SD 4.78), 194 061 (45.31%) were nulliparous, and 6.3% (n = 26 971) conceived with MAR. We examined the association of BMI and MAR with the following composite primary outcomes: 'uncomplicated pregnancy and birth' and 'healthy baby'. We conducted Poisson regression and adjusted for maternal age, parity, gestational weight gain, smoking and previous caesarean section. MAIN RESULTS AND THE ROLE OF CHANCE: In our study, 36.80% (n = 157 623) of women had an uncomplicated pregnancy and birth according to the definition used. The predicted probability of having an uncomplicated pregnancy and birth for women with a BMI of 25 kg/m2 who conceived spontaneously was 0.33 (0.32 to 0.35), while it was 0.28 (0.24 to 0.32) for women who used hormonal stimulation and 0.26 (0.22 to 0.29) for women who used IVF/ICSI. This probability reduced with increasing BMI category for both MAR and non-MAR users. For women with a BMI of 30 kg/m2, the predicted probability of having an uncomplicated pregnancy and birth was 0.28 (0.26 to 0.30) for women who conceived spontaneously, and 0.22 (0.16 to 0.29) and 0.20 (0.14 to 0.26) for women who used hormonal stimulation only or IVF/ICSI, respectively. The predicted probability of having a healthy baby for women with a BMI of 25 kg/m2 who conceived spontaneously was 0.92 (0.91 to 0.93), 0.89 (0.87 to 0.92) for women who used hormonal stimulation only and 0.85 (0.84 to 0.87) for women who used IVF/ICSI. LIMITATIONS, REASONS FOR CAUTION: The database did not include data on socio-economic status, pre-pregnancy morbidities and paternal BMI. Subsequently, we could not adjust for these factors in the analysis. WIDER IMPLICATIONS OF THE FINDINGS: Obese women who use MAR are at the highest risk of pregnancy and birth complications. This increase in interventions also has cost and resource implications which is relevant for funding policies. Weight loss interventions prior to MAR seem plausible but their (cost-) effectiveness needs urgent investigation. STUDY FUNDING/COMPETING INTEREST(S): F.W. received an Erasmus Plus training grant to visit A.B., L.A. and R.D. and conducted this study during this visit. The authors have no competing interest to declare. TRIAL REGISTRATION NUMBER: N/A.

Factors influencing pregnancy outcome with special attention to modified slow-release insemination and a patient-centred approach in a donor insemination programme: a prospective cohort study.

Introduction: A higher pregnancy rate after slow-release insemination instead of bolus injection was described in previous studies. Besides an effective medical treatment most patients wish to receive a patient-centred approach with sufficient emotional support. Study question: Does a patient-friendly approach with slow-release insemination (SRI) increase the clinical pregnancy rate (CPR) after intrauterine insemination (IUI) with donor semen? Study design, size, duration: The data of an ongoing prospective cohort study were analysed investigating the results of 1995 donor inseminations in 606 women from July 2011 until December 2018. As from January 2016 the insemination procedure was performed by midwives instead of medical doctors. Instead of bolus injection of sperm a slow-release IUI was done together with a more patient-centred approach. Materials and Methods: The data of 1995 donor inseminations were analysed to study the importance of different covariates influencing IUI success. Generalized estimating equations (GEEs) were used for statistical analysis. Results of two periods (2011-2015 and 2016-2018) were examined and compared. Results: Clinical pregnancy rates (with foetal heartbeat) following donor inseminations increased from 16.6 % to 20.8 % per cycle, a non-significant increase (p=0.061). Conclusion: A more patient-friendly approach with slow-release of processed semen resulted in a non-significant higher clinical pregnancy rate of 4.2 % per cycle after donor insemination.

Simplified sperm testing devices: a possible tool to overcome lack of accessibility and inconsistency in male factor infertility diagnosis. An opportunity for low- and middle- income countries.

BACKGROUND: Manual semen assessment (MSA) is a key component in a male's fertility assessment. Clinicians rely on it to make diagnostic and treatment decisions. When performed manually, this routine laboratory test is prone to variability due to human intervention which can lead to misdiagnosis and consequently over- or under- treatment. For standardisation, continuous training, quality control (QC) programs and pricy Computer-Assisted Sperm Analysis (CASA) systems have been proposed, yet, without resolving intra- and inter-laboratory variability. In response, promising simplified sperm testing devices, able to provide cost-effective point-of-care male infertility diagnosis are prospected as a plausible solution to resolve variability and increase access to sperm testing. MATERIALS AND METHODS: A throughout literature research for semen testing, sperm analysis, smart-phone assisted semen analysis, 'at-home' semen testing, male infertility, infertility in developing countries, infertility in low- and middle-income countries (LMIC) and quantitative sperm analysis was performed. A total of 14 articles, specific to 'at-home' simplified sperm assessment, were included to treat the core subject. RESULTS: Continuous training and consistent QC, are sine qua none conditions to achieve accurate and comparable MSA. Compliance does not rule-out variability, nevertheless. Emerging simplified sperm assessment devices are an actual alternative to resolve the lack of standardisation and accessibility to sperm analysis. YO ® , SEEM ® , and ExSeed ® are commercially available, user-friendly smartphone-based devices which can accurately measure volume, sperm concentration (millions/ml) and total motile sperm count. More broadly, by cost-effectiveness, availability, accuracy and convenient application, these devices could effectively select patients for first-line artificial reproduction treatments such as intrauterine insemination. CONCLUSIONS: Accuracy and cost-effectiveness make smart-phone based sperm testing devices a practical and realistic solution to overcome variability in MSA. Importantly, these tools represent an actual opportunity to standardise and improve male subfertility diagnosis and treatment, especially in LMIC. However, before clinical application is possible, guidelines, further testing with special attention on accuracy in washed sperm, availability, cost-benefit and reliability are required.

Improving IUI success by performing modified slow-release insemination and a patient-centred approach in an insemination programme with partner semen: a prospective cohort study.

BACKGROUND: Pregnancy rates after in vitro fertilisation (IVF) treatment continue to improve, while intrauterine insemination (IUI) programmes show no such trend. There is a need to improve success rates with IUI to retain it as a viable option for couples who prefer avoiding IVF as a first line treatment. OBJECTIVE: To investigate if a modified slow-release insemination (SRI) increases the clinical pregnancy rate (CPR) after intrauterine insemination (IUI) with partner semen. MATERIALS AND METHODS: This was a prospective cohort study in a Belgian tertiary fertility centre. Between July 2011 and December 2018, we studied data from an ongoing prospective cohort study including 989 women undergoing 2565 IUI procedures for unexplained or mild/moderate male infertility. These data were analysed in order to study the importance of different covariates influencing IUI success. Generalised estimating equations (GEEs) were used for statistical analysis. Results of two periods (2011-2015, period 1 and 2016-2018, period 2) were examined and compared. From January 2016 (period 2) onwards, a standardised SRI procedure instead of bolus injection of sperm was applied. The primary outcome parameter was the difference in clinical pregnancy rate (CPR) per cycle between period 1 (bolus IUI) and period 2 (modified SRI). Secondary outcome results included all other parameters significantly influencing CPR after IUI. RESULTS: Following the application of modified SRI the CPR increased significantly, from 9.03% (period 1) to 13.52% (period 2) (p = 0.0016). Other covariates significantly influencing CPR were partner's age, smoking/non-smoking partner, BMI patient, ovarian stimulation protocol and Inseminating Motile Count (after semen processing). CONCLUSIONS: Conclusions: The intentional application of modified slow-release of processed semen appears to significantly increase CPRs after IUI with homologous semen. Future studies should investigate whether SRI, patient-centred measures, or a combination of both, are responsible for this improvement.

IVF in Africa: what is it all about?

Infertility is a universal problem with the highest prevalence in low-resource countries, particularly in sub-Saharan Africa where infection-related tubal damage is the commonest cause. It is estimated that more than 180 million couples in developing countries suffer from primary or secondary infertility. In most African countries, the social stigma of childlessness still leads to isolation and abandonment. Differences between the developed and developing world are emerging because of the different availability in infertility care and the different socio-cultural value surrounding procreation and childlessness. Although reproductive health education and prevention of infertility are number one priorities, the need for accessible diagnostic procedures and affordable assisted reproductive technologies (ART) is very high. The success and sustainability of ART in resource-poor settings will depend, to a large extend, on our ability to optimise these techniques in terms of availability, affordability and effectiveness. Different new innovations and techniques can make the diagnostic work-up and treatment through assisted reproductive technologies (ART), including in-vitro fertilization (IVF), more affordable. These include automated smartphone-based assays for semen analysis and simplified IVF culture systems. The initiative of African Network and Registry for Assisted Reproductive Technology (ANARA) to register all IVF cycles in Africa needs our support and will be of paramount importance in the future. The hurdles to implement ART in most African countries are numerous and although more and more IVF centres are founded, the accessibility to ART remains very low.

Oocyte insemination with the Walking Egg simplified IVF culture system - an investigation into reduced sperm numbers, sperm DNA fragmentation and reactive oxygen species formation.

RESEARCH QUESTION: What is the lowest number of sperm that can be used for oocyte insemination during either conventional or the Walking Egg simplified IVF? Does the use of low numbers of sperm in high volume (1 ml) culture media have an effect on sperm DNA fragmentation and reactive oxygen species formation? Also, does the extended co-incubation of embryos with sperm and cumulus cells in the Walking Egg culture tubes induce higher levels of reactive oxygen species? DESIGN: Binding of sperm to the zona pellucida was compared using a modified hemi-zona assay. In the first part of the study, the binding capacity of decreasing concentrations of motile spermatozoa was evaluated, followed by a comparison of sperm binding after simulated insemination by conventional or the Walking Egg simplified culture protocol. Sperm DNA fragmentation was determined between test and control samples in the second part of the study and reactive oxygen species was measured in spent culture media. As a supplementary examination, reactive oxygen species formation, with the simulated co-incubation of cumulus and sperm cells, was compared between the conventional and Walking Egg IVF culture systems. RESULTS: Sperm-zona binding in 50 µl culture media, indicated mean sperm binding of more than 20 sperm per hemi-zona with as low as 1000 sperm used for insemination. Using a higher volume of culture media, as is done in the Walking Egg simplified IVF culture system, resulted in 42.8% reduced sperm-zona binding. No significant difference in DNA integrity was observed between the two test groups. The amount of ROS generated during conventional IVF in the first 18 hours of incubation was more than that produced in the simplified culture system over sixty-six hours. Only during extended culture for 114 hours in the simplified culture system, did the ROS generated slightly surpass that of conventional IVF at 18 hours. CONCLUSION: Oocyte insemination with as little as 2 x 103 motile sperm showed sufficient sperm-zona binding capacity to be indicative of fertilization potential, supporting the Walking Egg simplified IVF insemination protocol. No difference in DNA fragmentation was observed between conventional and the simplified IVF culture systems, while reactive oxygen species formation was indicated to be at a slower rate during incubation with the Walking Egg simplified IVF culture system than with conventional IVF.

Time has come to include Human Papillomavirus (HPV) testing in sperm donor banks.

HPV is well known as a potential cause of cervical cancer. Less well known is its link to temporal subfertility that is caused by binding of infectious virions to the spermatozoa's head which induces sperm-DNA damage and causes a reduction in clinical pregnancy rates in women receiving HPV positive semen. This impact on the global fertility burden remains greatly underestimated and underexplored. This risk of reduced fertility due to infectious HPV in sperm is especially important when donor sperm insemination is considered, since testing for the presence of HPV virions before use seems warranted. We tested 514 donor sperm samples from 3 different sperm banks for 18 different HPV types. Overall 3.9% (20/514) of tested donor sperm was positive for HPV, with different prevalence among the 3 different sperm banks (3.6% bank A, 3.1% bank B and 16.7% bank C). Also the HPV virion per spermatozoon ratio in donor samples was similar across the different sperm banks (95% CI 0,01 to 1,07 HPV virions/spermatozoon). When HPV positive donor sperm was used, no clinical pregnancies resulted, whereas when HPV negative donor sperm was used the clinical pregnancy rate was 14.6%. From both a cost/benefit and a safety point of view we recommend that donor sperm should always be tested for HPV before using it for insemination.

Influence of BMI and smoking on IUI outcome with partner and donor sperm.

There is limited literature on the influence of smoking and BMI on success rates after intrauterine insemination (IUI). As a result of a prospective cohort study we could investigate data from 1401 IUI cycles with partner semen and 1264 IUI cycles with donor semen, primary outcome being clinical pregnancy rate (CPR). Univariate statistical analysis showed significant influence of female BMI on clinical pregnancy in the partner insemination group (CPR of 6,5%, 8%, 16,3% and 9,4% for a female BMI < 20, 20-24.9, 25-29.9 and 3 30, p=0.032), while in the donor group this in uence was not signi cant (CPR respectively 11.1% (BMI< 20), 18.5% (20-24.9), 18.0% (25-29.9) and 14.7% for BMI 3 30). Multivariate analysis through generalized estimating equations (GEE) could not confirm this significant influence of female BMI on fecundity in the partner semen group. For smoking, univariate statistical analysis revealed male smoking to be a negative influence for the clinical pregnancy rate in the partner insemination group (10.9% CPR in couples with male non-smokers versus 5.9% with male partners smoking 1-14 cig/day, p=0.017). After multivariate GEE analysis this result remained significant (p< 0,01). In the donor semen group female non-smoking or smoking less than 15 cigarettes a day turned out to be significantly associated with a higher CPR compared to women smoking more than 15 cigarettes daily (16.8% and 24.5% versus 5.6%, p=0,01). These results were also significant after multivariate GEE analysis (p= 0,047 and p= 0,02).

Global reproductive health - Why do we persist in neglecting the undeniable problem of childlessness in resource-poor countries?

The consequences of involuntary childlessness in developing countries create more wide-ranging societal problems compared to Western societies, particularly for women. Negative psychosocial and economical consequences for childless couples are often severe and underestimated by the local and international society. Infertility treatment is often limited to certain procedures and certain costumers. Most common arguments against supporting infertility care in resource-poor countries are the "overpopulation" and the "limited resources" argument, but they totally neglect the reproductive rights and systematic exclusion of millions of women from the right to reproduce. Because ART procedures are very expensive, governments and international aid-organisations are currently not investing in this technique. But the scene has changed recently: inexpensive ovarian stimulation protocols for IVF have proven their value and simplified but high quality low cost IVF techniques are available nowadays. From an ethical point of view it is our belief that the community can no longer justify the systematic exclusion of one tenth of couples from the right to reproduce in resource-poor countries.

Perfusion of the uterine junctional zone in nulliparous and primiparous women assessed by DCE-MRI, as a function of menstrual cycle and hormonal contraception.

PURPOSE: To evaluate the perfusion parameters of inner and outer myometrium in healthy nulliparous and primiparous women who are and who are not currently using hormonal contraceptives by means of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). MATERIAL AND METHODS: We performed pelvic 1.5T DCE-MRI on 98 women: 18 nulliparous non-users, 30 nulliparous users, 12 primiparous non-users and 38 primiparous users of hormonal contraception (mean age respectively 26.4, 25.8, 30.23 and 28.18years). The nulliparous non-users underwent DCE-MRI investigations during their follicular, ovulatory and luteal phase. Perfusion parameters (iAUC/volume, Ktrans, Kep and Ve) were assessed in the anterior and posterior junctional zone (JZ), outer myometrium and cervix. RESULTS: In nulliparous non-users, the mean Ktrans and iAUC/volume showed a decrease from follicular to luteal phase (0.82 vs 0.55min-1 for Ktrans, p=0/027 and 1.28 vs 0.68 for iAUC/volume, p<0.001). The anterior JZ demonstrated lower Ktrans (p=0.050) and higher Kep (p=0.012), in nulliparous non-users, lower Ktrans in nulliparous users (p<0.001) and lower Ve in primiparous users (p=0.012) than the anterior outer myometrium. Ktrans at the anterior and posterior JZ wall in nulliparous users was lower than in non-users (p=0.001 and p=0.013) and Ve at the anterior JZ wall in primiparous users was lower than in non-users (p=0.044). CONCLUSION: This study provides data on normal perfusion parameters of inner and outer myometrium, which may be potentially useful in assisted reproductive therapy.

The prognostic value of perifollicular blood flow in the outcome after assisted reproduction: a systematic review.

BACKGROUND: The overall final outcome of assisted reproductive technologies (ART) is still more often a failure than a success. Assessing perifollicular blood flow (PFBF) is one technique to predict and possibly improve this outcome. The aim was to provide a structured review of studies concerning PFBF and its prognostic value in patients undergoing ART, including IUI (intrauterine insemination). METHODS: PUBMED, EMBASE and Cochrane Database of Systematic Reviews were searched for relevant studies published until December 2016. As key words 'Perifollicular blood flow', 'IUI', 'IVF' and 'ICSI' were used. RESULTS: A total of 14 articles were included in the current review. The results are very heterogeneous, though there is evidence that measuring PFBF could be a good prognostic marker for oocyte and embryo quality, but even more for pregnancy rate after IVF/ICSI. This finding is not observed in studies concerning IUI. CONCLUSIONS: Our results highlight an urgent need to investigate the role for PFBF assessment by Power Doppler in ART in randomised controlled trials.

What does a clinically-scientific professional society stand for?

Originated as a mainly social group of befriended colleagues, the VVOG has evolved over the past 55 years to become a truly professional society facing successfully such diverse challenges as organizing scientific congresses, postgraduate training, ethical debates, hands-on training courses, social events, interactions with national and international sister societies but also with the industry, insurers, the government, politicians and patient organisations.

The Walking Egg Project: how to start a TWE centre?

The main objective of the Walking Egg non-profit organization is the implementation of good quality and affordable infertility centres in resource-poor countries. Three levels of assistance are suggested: A level 1 infertility clinic is a basic infertility clinic capable of offering semen analysis, hormonal assays, follicular scanning, ovulation induction and intrauterine inseminations. Level 2 infertility clinics are supposed to perform simplified IVF as well. Level 3 infertility clinics capable of offering ICSI, cryopreservation and operative endoscopy are not part of the Walking Egg Project in the initial phase. A high quality but affordable service delivery with special attention to the prevention of complications and unnecessary interventions should be the trademark of this project.

The twin epidemic in infertility care - Why do we persist in transferring too many embryos?

The epidemic of iatrogenic multiple births as a result of infertility treatment are responsible for an unacceptable high incidence of maternal, perinatal and childhood morbidity and mortality. Healthcare costs due to infertility therapy are too high and this may lead to social and political concern. The introduction of single embryo transfer (SET) was a real breakthrough, but was only accepted in most European countries and Japan. The United States, Latin America and most developing countries still have high multiple pregnancy rates. The most common argument for not performing SET are the high costs associated with ART procedures. Competition between ART centres to achieve and publish the highest success rates is another major factor. But things have changed: vitrification methods for cryopreservation are responsible for a better survival and increased success rate with frozen-embryo transfer, our knowledge to select the best embryo for SET is increasing and the growing concern of health care providers and governments can be expected in the near future. Infertility specialists are supposed to deliver healthy, preferably singleton babies at the lowest cost. Misuse of science still reveals the dark side of ART in too many centres. There is enough evidence that reimbursement policies providing accessible ART to infertile couples can decrease the potential harm from multiple pregnancies substantially unless we succeed to provide simplified IVF at affordable prices.

Pregnant after assisted reproduction: a risk pregnancy is born! 18-years perinatal outcome results from a population-based registry in Flanders, Belgium.

BACKGROUND: Although the increased risk for perinatal morbidity and mortality of babies born after ART is largely attributed to a higher rate of multiple gestations, a significantly worse perinatal outcome for singleton pregnancies following ART compared to pregnancies after natural conception has been reported as well. Most studies only include IVF/ICSI pregnancies; studies describing the perinatal outcome of pregnancies after non-IVF assisted reproduction are scarce. METHODS AND MATERIALS: Population-based cohort study with three exposure groups: a study group of pregnancies (1) after ovarian stimulation (OS), with or without artificial insemination (AI), (2) after IFV or ICSI and (3) a naturally conceived (NC) comparison group. Data from the regional registry of all hospital deliveries in the Dutch-speaking part of Belgium during an 18-years period from January 1993 until December 2010 were used. The perinatal outcome parameters were prematurity, low birth weight, perinatal mortality and morbidity including neonatal intracranial bleeding and need for intubation. Logistic regression analysis was used including mode of conception, female age, foetal sex, parity and year of delivery. RESULTS: Data on 1 079 814 births were studied: 1 039 415 singletons (19 896 IVF/ICSI, 20 469 OS and 999 050 NC) and 39 041 twins (9 353 IVF/ICSI, 4812 OS and 24 876 NC) were available for analysis. IVF/ICSI singletons had a significantly worse outcome when compared to OS and NC for almost all investigated perinatal parameters. Non-IVF/OS singletons were also significantly disadvantaged for prematurity and low birth weight when compared to NC. The outcome of twin pregnancies was similar for the three groups unless only unlike-sex twins were studied separately. Among this subgroup, IVF/ICSI carried a higher risk for low birth weight when compared to NC. OS unlike-sex twins were at increased risk for low birth weight, intra uterine death and perinatal mortality when compared to NC. CONCLUSION: According to our results all ART pregnancies, whether due to IVF/ICSI or non-IVF treatment, have to be considered as risk pregnancies, irrespective of the number of foetuses. LIMITATIONS OF THE STUDY: Although our logistic regression analysis included co-variables with a potential impact on perinatal outcome such as mode of conception, female age, foetal sex, parity and year of delivery, we couldn't correct for other prominent confounders such as the use of fresh or frozen embryos, use of homologous or donor gametes, smoking, obesity, socio-economic status, occupation exposures and pre-existing disease.

Artificial insemination history: hurdles and milestones.

Artificial insemination with homologous (AIH) or donor semen (AID) is nowadays a very popular treatment procedure used for many subfertile women worldwide. The rationale behind artificial insemination is to increase gamete density at the site of fertilisation. The sequence of events leading to today's common use of artificial insemination traces back to scientific studies and experimentation many centuries ago. Modern techniques used in human artificial insemination programmes are mostly adapted from the work on cattle by dairy farmers wishing to improve milk production by using artificial insemination with sperm of selected bulls with well chosen genetic traits. The main reason for the renewed interest in artificial insemination in human was associated with the refinement of techniques for the preparation of washed motile spermatozoa in the early years of IVF. The history of artificial insemination is reviewed with particular interest to the most important hurdles and milestones.

'Fertility Awareness-Based Methods' and subfertility: a systematic review.

Fertility awareness based methods (FABMs) can be used to ameliorate the likelihood to conceive. A literature search was performed to evaluate the relationship of cervical mucus monitoring (CMM) and the day-specific -pregnancy rate, in case of subfertility. A MEDLINE search revealed a total of 3331 articles. After excluding articles based on their relevance, 10 studies and were selected. The observed studies demonstrated that the cervical mucus monitoring (CMM) can identify the days with the highest pregnancy rate. According to the literature, the quality of the vaginal discharge correlates well with the cycle-specific probability of pregnancy in normally fertile couples but less in subfertile couples. The results indicate an urgent need for more prospective randomised trials and -prospective cohort studies on CMM in a subfertile population to evaluate the effectiveness of CMM in the subfertile couple.