A critical systematic review and meta-analyses of risk factors for fertility problems in a globalized world.

Globally, fertility awareness efforts include well-established risk factors for fertility problems. Risks disproportionately affecting women in the Global South, however, are neglected. To address this gap, we conducted a systematic review and meta-analyses of relevant risk factors to examine the association between risk factors and fertility problems. MEDLINE, Embase, Cochrane Library, regional databases and key organizational websites were used. Three authors screened and extracted data independently. Studies assessing exposure to risk (clinical, community-based samples) were included, and studies without control groups were excluded. Outcome of interest was fertility problems, e.g. inability to achieve pregnancy, live birth, neonatal death depending on study. The Newcastle-Ottawa Scale was used to assess study quality. A total of 3843 studies were identified, and 62 were included (58 in meta-analyses; n = 111,977). Results revealed the following: a ninefold risk of inability to become pregnant in genital tuberculosis (OR 8.91, 95% CI 1.89 to 42.12); an almost threefold risk in human immunodeficiency virus (OR 2.93, 95% CI 1.95 to 4.42) and bacterial vaginosis (OR 2.81, 95% CI 1.85 to 4.27); a twofold risk of tubal-factor infertility in female genital mutilation/cutting-Type II/III (OR 2.06, 95% CI 1.03 to 4.15); and postnatal mortality in consanguinity (stillbirth, OR 1.28, 95% CI 1.04 to 1.57; neonatal death, OR 1.57, 95% CI 1.22 to 2.02). It seems that risk factors affected reproductive processes through multiple pathways. Health promotion encompassing relevant health indicators could enhance prevention and early detection of fertility problems in the Global South and disproportionately affected populations. The multifactorial risk profile reinforces the need to place fertility within global health initiatives.

The impact of religion and culture on medically assisted reproduction in the Middle East and Europe.

Infertility is a medico-socio-cultural problem associated with gender-based suffering. Infertility treatment, including assisted reproductive technology (ART), is a human right. Culture and religion were among the stumbling blocks to early acceptance of ART, particularly in the Middle East and to a lesser extent in Europe. This was mostly due to the different cultural and religious perspectives on the moral status of the embryo in the two regions and the concerns about what could be done with human embryos in the laboratory. There is an increased demand for ART in both the Middle East and Europe, although the reasons for this increased demand are not always the same. Although Europe leads the world in ART, there is an unmet need for ART in many countries in the Middle East. Where ART is not supported by governments or insurance companies, a large percentage of couples paying for ART themselves will stop before they succeed in having a baby. There are similarities and differences in ART practices in the two regions. If a healthcare provider has a conscientious objection to a certain ART modality, he/she is ethically obliged to refer the patient to where they could have it done, provided it is legal.

GnRH agonist plus vaginal progesterone for luteal phase support in ICSI cycles: a randomized study.

In this prospective randomized study, the effect of daily gonadotrophin-releasing hormone agonist (GnRHa) in the luteal phase on IVF and intracytoplasmic sperm injection (ICSI) outcomes was assessed. Women (n = 446) were counselled for IVF-ICSI, and randomized on the day of embryo transfer to group 1 (daily 0.1 mg subcutaneous GnRHa until day of beta-HCG) (n = 224) and group 2 (stopped GnRHa on day of HCG injection) (n = 222). Both groups received daily vaginal progesterone suppositories. Primary outcome was clinical pregnancy rate. Secondary outcome was ongoing pregnancy rate beyond 20 weeks. Mean age, oestradiol on day of HCG, number of oocytes retrieved, number of embryos transferred, and clinical and ongoing pregnancy rates were 28.9 ± 4.5 years, 2401 ± 746 pg/mL; 13.5 ± 6.0 oocytes; 2.6 ± 0.6 embryos, and 36.2% and 30.4% consecutively in group 1 compared with 29.7 ± 4.7 years, 2483 ± 867 pg/mL, 13.7 ± 5.5 oocytes, 2.7 ± 0.6 embryos, 30.6% pregnancy rate, and 25.7% ongoing pregnancy rate in group 2. No significant difference was found between the groups. Subcutaneous GnRHa during the luteal phase of long GnRHa protocol cycles does not increase clinical or ongoing pregnancy rates after IVF-ICSI.

Phase IV, open-label, randomized study of low-dose recombinant human follicle-stimulating hormone protocols for ovulation induction.

BACKGROUND: This Phase IV, open-label, multicentre, randomized study (MEnTOR) compared two low-dose recombinant human follicle-stimulating hormone (r-hFSH) protocols for ovulation induction. METHODS: This study was conducted in six Middle Eastern countries between March 2009 and March 2011. Eligible women (18-37 years), with World Health Organization Group II anovulatory infertility, were randomized to receive r-hFSH (starting daily dose: 75 IU) as a chronic low-dose (CLD) (37.5 IU dose increase on Day 14) or low-dose (LD) (37.5 IU dose increase on Day 7) protocol if no follicles were ≥ 10 mm. The maximum r-hFSH daily dose permitted was 225 IU/day. The total length of ovarian stimulation could not exceed 35 days, unless ultrasound assessment suggested imminent follicular growth and maturation. Patients underwent only one treatment cycle. Primary endpoint: incidence of mono-follicular development. Secondary endpoints included: stimulation duration and rates of bi-follicular development; human chorionic gonadotrophin administration rate; clinical pregnancy; and cycle cancellation (owing to inadequate response). Adverse events (AEs) were recorded. The primary efficacy analysis was performed using data from all patients who received at least one dose of correct study medication, had at least one efficacy assessment, and no protocol violations at treatment start (CLD group, n=122; LD group, n=125). RESULTS: Mono-follicular development rates (primary endpoint) were similar in both groups (CLD: 56.6% [69/122] versus LD: 55.2% [69/125], p=0.93; primary efficacy analysis population). Similarly, there were no significant differences between groups in bi-follicular development, clinical pregnancy or cycle cancellation (inadequate response) rates. In patients who received human chorionic gonadotrophin injections, the mean duration of stimulation was 13.7 days in the CLD group and 12.9 days in the LD group. Clinical pregnancy rates for those patients who received an hCG injection were similar in both groups (CLD: 20.2% [19/94] versus LD: 19.8% [18/91], p=0.94; primary efficacy analysis population). Most AEs were mild in severity. Only one case of ovarian hyperstimulation syndrome was reported (mild; CLD group). CONCLUSIONS: Efficacy and safety outcomes were similar for the two protocols.

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

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

Islam, medicine, and Arab-Muslim refugee health in America after 9/11.

Islam is the world's second largest religion, representing nearly a quarter of the global population. Here, we assess how Islam as a religious system shapes medical practice, and how Muslims view and experience medical care. Islam has generally encouraged the use of science and biomedicine for the alleviation of suffering, with Islamic authorities having a crucial supportive role. Muslim patients are encouraged to seek medical solutions to their health problems. For example, Muslim couples who are infertile throughout the world are permitted to use assisted reproductive technologies. We focus on the USA, assessing how Islamic attitudes toward medicine influence Muslims' engagement with the US health-care system. Nowadays, the Arab-Muslim population is one of the fastest growing ethnic-minority populations in the USA. However, since Sept 11, 2001, Arab-Muslim patients--and particularly the growing Iraqi refugee population--face huge challenges in seeking and receiving medical care, including care that is judged to be religiously appropriate. We assess some of the barriers to care--ie, poverty, language, and discrimination. Arab-Muslim patients' religious concerns also suggest the need for cultural competence and sensitivity on the part of health-care practitioners. Here, we emphasise how Islamic conventions might affect clinical care, and make recommendations to improve health-care access and services for Arab-Muslim refugees and immigrants, and Muslim patients in general.

The use of vaginal natural progesterone for prevention of preterm birth in IVF/ICSI pregnancies.

The aim of this study was to evaluate the effect of vaginal natural progesterone on the prevention of preterm birth in IVF/intracytoplasmic sperm injection (ICSI) pregnancies. A single-centre prospective placebo-controlled randomized study was performed. A total of 313 IVF/ICSI pregnant patients were randomized into two groups for either treatment with daily 400 mg vaginal natural progesterone or placebo, starting from mid-trimester up to 37 weeks or delivery. Amongst the patients, there were 215 singleton and 91 twin pregnancies. There was no significant difference in risk of preterm birth among all patients (OR 0.672, 95% CI 0.42-1.0. There was a significantly lower preterm birth rate in singleton pregnancies in the natural progesterone arm (OR 0.53, 95% CI 0.28-0.97) and no significant difference between both arms in twin pregnancies (OR 0.735, 95% CI 0.36-2). In conclusion, the administration of 400 mg vaginal natural progesterone from mid trimester reduced the incidence of preterm birth in singleton, but not in twin, IVF/ICSI pregnancies.

Third-party reproductive assistance around the Mediterranean: comparing Sunni Egypt, Catholic Italy and multisectarian Lebanon.

The article examines religious and legal restrictions on third-party reproductive assistance in three Mediterranean countries: Sunni Egypt, Catholic Italy and multisectarian Lebanon. In Egypt, assisted reproduction treatments are permitted, but third parties are banned, as in the rest of the Sunni Islamic world. Italy became similar to Egypt with a 2004 law ending third-party reproductive assistance. In multisectarian Lebanon, however, the Sunni/Catholic ban on third-party reproductive assistance has been lifted, because of Shia rulings emanating from Iran. Today, third-party reproductive assistance is provided in Lebanon to both Muslims and Christians, unlike in neighbouring Egypt and Italy. Such comparisons point to the need for understanding the complex interactions between law, religion, local moralities and reproductive practices for global bioethics.

Ultrasound cervical measurement and prediction of spontaneous preterm birth in ICSI pregnancies: a prospective controlled study.

A prospective controlled study was performed in which transvaginal ultrasound measurement of cervical length was compared in 222 twin ICSI pregnancies, 122 singleton ICSI pregnancies and 51 spontaneous singleton pregnancies. Preterm birth was defined as

Highly purified hMG achieves better pregnancy rates in IVF cycles but not ICSI cycles compared with recombinant FSH: a meta-analysis.

OBJECTIVE: Human menopausal gonadotropin (hMG) was demonstrated to be superior to recombinant FSH (rFSH) regarding clinical outcomes. It is not clear whether this change in the evidence was due to the introduction of highly purified (HP) hMG. DESIGN: Systematic review of properly randomised trials comparing HP-hMG vs. rFSH in women undergoing in vitro fertilisation (IVF) and/or intracytoplasmic sperm injection (ICSI). A meticulous search was performed using electronic databases and hand searches of the literature. RESULTS: Six trials (2371 participants) were included. Pooling of the trials demonstrated that the probability of clinical pregnancy following HP-hMG administration was higher than rFSH and reached borderline significance (odd ratio (O.R) = 1.21, 95% confidence interval (CI) = 1.00 to 1.45), but the ongoing pregnancy/live-birth rate was not statistically different between the two drugs, although it showed strong trends towards improvement with HP-hMG (O.R = 1.19, 95% CI = 0.98 to 1.44). Subgroup analysis comparing both drugs in IVF cycles demonstrated a statistically significant better ongoing pregnancy/live-birth rate in favour of HP-hMG (O.R = 1.31, 95% CI = 1.02 to 1.68). On the other hand, there was almost an equal ongoing pregnancy/live-birth rate in ICSI cycles (OR = 0.98, 95% CI = 0.7 to 1.36). CONCLUSIONS: HP-hMG should be preferred over rFSH in women undergoing assisted reproduction, especially if IVF is the intended method of fertilisation.

Prospective randomized study comparing luteal phase support for ICSI patients up to the first ultrasound compared with an additional three weeks.

BACKGROUND: There is a consensus that administration of progesterone to women after IVF for luteal phase support (LPS) is associated with a higher ongoing pregnancy rate. However there are few studies, including only one randomized study, which have examined the optimal duration of LPS. METHODS: A questionnaire concerning details of LPS was returned from 21 leading IVF centres. We then randomized 257 women, who were pregnant after ICSI on day of first ultrasound, into two groups: to continue LPS for three more weeks or to stop on the day of ultrasound. RESULTS: The duration of LPS in the questionnaire varied from the day of positive pregnancy test up to 12 weeks of pregnancy in different centres. In the randomized study, 132 patients in Group A continued LPS for 3 weeks after first ultrasound, whereas 125 patients in Group B stopped LPS on day of first ultrasound. After confirming pulsations, the miscarriage rate up to 20 weeks of gestation was 4.6% (6/132) in group A and 4.8% (6/125) in group B [odds ratios (OR) = 0.94; 95% confidence intervals (CI) = 0.3-3.1]. Bleeding episodes were 15.9% in Group A compared with 20.8% in group B (OR = 0.72; 95% CI = 0.38-1.36). CONCLUSIONS: There is no international consensus about the duration of LPS; our single-centre randomized trial did not support extending the LPS beyond the day of first ultrasound demonstrating echoes and pulsations. Trials registry number-ISRCTN: 88722916.

Ethical issues in infertility.

Infertility is a global medico-socio-cultural problem with gender-based suffering particularly in developing countries. Conventional methods of treatment for infertility do not usually raise ethical concerns. However, assisted reproductive technology (ART) has initiated considerable ethical debate, disagreement, and controversy. There are three ethical principles that provide an ethical basis for ART: the principle of liberty, principle of utility, and principle of justice. Medical ethics are based on the moral, religious, and philosophical ideas and principles of the society and are influenced by economics, policies, and law. This creates tension between the principles of justice and utility, which can result in disparity in the availability of and access to ART services between the rich and the poor. The moral status of the embryo is the key for all the ethical considerations and law regarding ART in different societies. This has resulted in cross-border ART. Conscientious objection of healthcare providers should not deprive couples from having access to a required ART service.

Does intrauterine injection of low-molecular-weight heparin improve the clinical pregnancy rate in intracytoplasmic sperm injection?

OBJECTIVE: Heparin can modulate proteins, and influence processes involved in implantation and trophoblastic development. This study aimed to assess the improvement of clinical pregnancy and implantation rates after local intrauterine injection of low-molecular-weight heparin (LMWH) in patients undergoing intracytoplasmic sperm injection (ICSI). METHODS: A randomised case/control design was followed in women scheduled for ICSI. The study arm was injected with intrauterine LMWH during mock embryo transfer immediately following the ovum pickup procedure, while the control arm was given an intrauterine injection with a similar volume of tissue culture media. Side effects, the clinical pregnancy rate, and the implantation rate were recorded. RESULTS: The pregnancy rate was acceptable (33.9%) in the LMWH arm with no significant reported side effects, confirming the safety of the intervention. No statistically significant differences were found in the clinical pregnancy and implantation rates between both groups (p=0.182 and p=0.096, respectively). The odds ratio of being pregnant after intrauterine injection with LMWH compared to the control group was 0.572 (95% confidence interval [CI], 0.27-1.22), while the risk ratio was 0.717 (95% CI, 0.46-1.13; p=0.146). No statistical significance was found between the two groups in other factors affecting implantation, such as day of transfer (p=0.726), number of embryos transferred (p=0.362), or embryo quality. CONCLUSION: Intrauterine injection of LMWH is a safe intervention, but the dose used in this study failed to improve the outcome of ICSI. Based on its safety, further research involving modification of the dosage and/or the timing of administration could result in improved ICSI success rates.

Selection of individual testicular tubules from biopsied testicular tissue with a stereomicroscope improves sperm retrieval rate.

The present study describes a new modification for testicular sperm extraction (TESE) with an intraoperative surgical loop, coupled with stereomicroscopic dissection in the laboratory, to identify sperm-containing tubules. The study included 116 consecutive patients with nonobstructive azoospermia (NOA) undergoing TESE and intracytoplasmic sperm injection. After dissection of testicular tissue under the stereomicroscope, patients were separated into 2 groups according to tubular diameter. In the first group (n = 72), all tubules were of the same diameter. In the second group (n = 44), tubules with variable diameters could be identified. In such cases, 1-2 of the most distended and opaque seminiferous tubules were selected and minced alone, then examined for the presence of spermatozoa. The rest of the testicular tissue suspension was minced and examined separately. In 11 (25%) cases, retrieved spermatozoa were found in the isolated distended tubules only. In 21 (47.7%) cases, spermatozoa were found in both the isolated distended tubules and the rest of the specimen. In 2 cases, spermatozoa were found only in the whole sample, not in the isolated tubules. In the remaining 10 cases, spermatozoa were not found in either the whole sample or the isolated tubules. The sperm recovery rate in the isolated tubules was significantly higher than that of the rest of the specimen (72.7% vs 52%, chi(2) = 3.93, P <.05), and larger numbers of spermatozoa could be easily retrieved in a shorter period of time. In conclusion, the selection and isolation of the most dilated and opaque seminiferous tubules by using the surgical loop, coupled with laboratory stereoscopic dissection, improves sperm retrieval for men with NOA. It is possible that surgical-loops TESE coupled with stereomicroscope may offer superior sperm retrieval when compared with conventional TESE and may also offer reduced operative time when compared with microdissection TESE.

Intracytoplasmic spermatid injection can result in the delivery of normal offspring.

Almost one-third of all patients with nonobstructive azoospermia undergoing testicular sperm extraction (TESE) and intracytoplasmic sperm injection (ICSI) have cancelled cycles due to failure to find spermatozoa. For these patients, every attempt should be made to rescue the cycles by searching for spermatids. In this retrospective study, we report our experience in using elongating (stage Sb2) and elongated (stage Sc and Sd1) spermatids for ICSI. The study included 488 consecutive ICSI and TESE cycles performed for 452 patients with nonobstructive azoospermia. In 179 (36.7%) cycles, neither spermatozoa nor mature spermatids (stage Sd2) suitable for injection were found. After an extensive search only Sb2, Sc, and Sd1 spermatids were found in 22 of these 179 cycles (12.3%). These spermatids were used for injection of retrieved oocytes. The fertilization rate was 33.2%, and 19 patients (86.4%) reached the embryo transfer stage. In 6 cycles a chemical pregnancy occurred, and 3 clinical pregnancies were established, resulting in the delivery of 3 healthy boys with normal karyotypes. When normal living spermatozoa or mature spermatids (stage Sd2) cannot be found during TESE, late spermatids (stage Sb2, Sc, and Sd1) can be used successfully and result in the delivery of healthy offspring.

Pregnancy rate is not improved by delaying embryo transfer from days 2 to 3.

OBJECTIVE: To compare the outcome of assisted reproduction in day 2 versus day three embryo transfer. DESIGN: Prospective study. PARTICIPANTS: A total of 927 consecutive embryo transfers for IVF and ICSI cycles including 626 embryo transfers on day 2 and 301 on day 3. INTERVENTION: IVF and ICSI. OUTCOME MEASURE: Clinical pregnancy rate. RESULTS: There is no significant difference in the pregnancy rate between ET on day 2 (50.9%) and ET on day 3 (50.5%). CONCLUSION: Embryo transfer could be done on days 2 or 3 according to the convenience of the patient and the medical team. CONDENSATION: Embryo transfer could be done on days 2 or 3 according to the convenience of the medical team with similar results.

The changing prevalence of infertility.

Infertility is a major, multifaceted issue worldwide whose prevalence is increasing in both high- and low-income countries. The reasons are numerous, and may differ among world regions, but lifestyle and nutritional factors, epidemic infections, and sexually transmitted diseases are major determinants in most latitudes. Three other reasons may explain the increasing incidence of infertility. First, owing to the widespread use of contraception, the choice of delaying the first pregnancy until the third decade of life places men and women at higher risk for sexually transmitted diseases, and women at higher risk for uterine fibroids, endometriosis, polycystic ovary syndrome, and chronic anovulation. Second, prolonged exposure to chronic stress and environmental pollutants may play a critical role in decreasing fertility. Third, gonadotoxic oncologic treatments allow many patients to survive cancer, at the cost of their fertility. This consideration may justify the development of treatments that preserve fertility.

Introduction: optimal in vitro fertilization in 2020: the global perspective.

This Views and Reviews series concerning future developments in in vitro fertilization will highlight various aspects of in vitro fertilization from the global perspective.