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.

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.

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.

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.

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.

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.

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.

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.

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.

The issue of reinfibulation.

Reinfibulation is resuturing after delivery or gynecological procedures of the incised scar tissue resulting from infibulation. Despite the global fight against female genital mutilation/cutting (FGM/C), reinfibulation of previously mutilated or circumcised women is still performed in various countries around the world. A good estimate of the prevalence of reinfibulation is difficult to obtain, but it can be inferred that 6.5-10.4million women are likely to have been reinfibulated worldwide. Women who undergo reinfibulation have little influence on the decision-making and are usually persuaded by the midwife or birth attendant to undergo the procedure immediately following labor or gynecological operation. Although medicalization of reinfibulation may reduce its immediate risks, it has no effect on the incidence of long-term risks. Reinfibulation is performed mainly for the financial benefit of the operator, and cultural values that have been perpetuated for generations. Reinfibulation has no benefits and is associated with complications for the woman and the unborn child. Its medicalization violates the medical code of ethics and should be abandoned. International and national efforts should be combined to eradicate this practice.

Healthcare workers and the brain drain.

The brain drain of health workers occurs mostly from low- and low/middle-income countries to resource-rich countries and from rural to urban areas. Shortage and uneven distribution of healthcare workers aggravated by the brain drain from Africa, Asia, and Pacific countries has contributed to impaired reproductive and sexual health services and the high rate of maternal and newborn mortality and morbidity in these counties. Brain drain impedes maternal, neonatal, and child health and the fight against HIV/AIDS, and translates into loss of potential employers, teachers, and role models. Source countries spend US$ 500 million each year to educate health workers who leave their home countries for North America, Western Europe, and South Asia. A code of practice on international recruitment of health personnel is needed. Improving the health workforce database, wages, health resources and working conditions, task shifting, pay-back from recipient countries and migrant health professionals, securing additional investment in the health workforce, and the development of locally relevant medical training and research are useful measures to combat this problem.