Is it time to establish age restrictions in ART?

Providers specializing in reproductive medicine are treating increasing numbers of women pursuing parenthood in their 40s, 50s, and beyond. The rise in later-life parenting can be linked to factors ranging from the advent of assisted reproductive technologies and donor oocytes to the highly publicized pregnancies of older celebrities. We explore the medical and psychosocial implications of this trend for both older parents and their children. We also discuss ethical arguments regarding older parents' access to fertility care, existing professional guidelines, and both public and provider opinions about setting age limits for fertility treatment. Finally, we share preliminary considerations of whether age policies should be established, applied to men as well as women, and standardized or considered on a case-by-case basis.

What are the risks of the assisted reproductive technologies (ART) and how can they be minimized?

Although assisted reproductive technologies (ART) have become established procedures performed around the world, there are still many unanswered questions regarding safety. Possible risks associated with infertility and ART include (1) those inherent to pregnancy, delivery, and childhood; (2) those associated with the infertility itself and its causes; and (3) risks iatrogenic to ART. Although there are many potential risks associated with ART, it has become clear that the major risk is multiple pregnancy and its consequences. Major efforts are warranted to reduce the risk of multiple gestations with IVF, but it is also clear that single-embryo transfer is not the solution in all cases. Moreover, several studies have now documented that perinatal outcomes are somewhat poorer in IVF singleton infants than in spontaneously conceived singletons, but it is not clear if this increased risk is due to the ART or the infertility. Concerns about the impact of abnormalities in genomic imprinting persist at this time, as do risks associated with the culture conditions and even our environment. Only time will tell if children born following ART are at any increased risk of developing certain chronic diseases as they age. In any case, the risks to IVF children and mothers are likely to remain higher than those for children and mothers conceived spontaneously without medical assistance. However, since there have been over 5 million births after ART worldwide, and the vast majority of pregnancies and children have been essentially "normal", it is obvious that any excess risk must be relatively small. The normality of most pregnancies mandates that extreme care be exercised in making any changes to current practice.

The history and future of in vitro fertilization in the United States: the complex interrelationships among basic science, human medicine, and politics.

Although much of the foundational basic scientific and clinical research was conducted in the United States, the first in vitro fertilization (IVF) birth occurred in the United Kingdom. Why? For centuries, all research surrounding the field of "reproduction" has elicited bipolar passionate responses by the American public, and the issue of "test tube babies" has been no different. The history of conception in the United States is defined by complex interrelationships among scientists, clinicians, and politically charged decisions by various branches of the US government. With a focus on research in the United States, this review summarizes the early scientific and clinical advances important to the development of IVF and then addresses the potential future developments in IVF. We also consider what future advances are possible in the United States given the current regulations, laws, and funding.

Executive summary of the Stages of Reproductive Aging Workshop +10: addressing the unfinished agenda of staging reproductive aging.

OBJECTIVE: The aim of this article is to summarize the recommended updates to the 2001 Stages of Reproductive Aging Workshop (STRAW) criteria. The 2011 STRAW +10 reviewed advances in understanding of the critical changes in hypothalamic-pituitary-ovarian function that occur before and after the final menstrual period. METHODS: Scientists from five countries and multiple disciplines evaluated data from cohort studies of midlife women and in the context of chronic illness and endocrine disorders on change in menstrual, endocrine, and ovarian markers of reproductive aging including antimüllerian hormone, inhibin-B, follicle-stimulating hormone, and antral follicle count. Modifications were adopted by consensus. RESULTS: STRAW +10 simplified bleeding criteria for the early and late menopausal transition, recommended modifications to criteria for the late reproductive stage (Stage -3) and the early postmenopause stage (Stage +1), provided information on the duration of the late transition (Stage -1) and early postmenopause (Stage +1), and recommended application regardless of women's age, ethnicity, body size, or lifestyle characteristics. CONCLUSIONS: STRAW +10 provides a more comprehensive basis for assessing reproductive aging in research and clinical contexts. Application of the STRAW +10 staging system should improve comparability of studies of midlife women and facilitate clinical decision making. Nonetheless, important knowledge gaps persist, and seven research priorities are identified.

Premature ovarian failure.

Premature ovarian failure is the term usually used to describe women aged younger than 40 years who present with amenorrhea, hypergonadotropinism, and hypoestrogenism. Such women may ovulate and even conceive after the diagnosis is made, so it may be more appropriate to refer to these patients as having "primary ovarian insufficiency," or alternatively, as having "hypergonadotropic hypogonadism" or "primary hypogonadism." The clinical presentation is diverse, and several different disorders can lead to premature ovarian failure. Affected women should be investigated for premutations of the FMR1 gene (causing fragile X syndrome in its fullest form) and for adrenal antibodies. Thyroiditis is the most frequent autoimmune disorder associated with premature ovarian failure and should be ruled out as well. Osteopenia is increased in women with premature ovarian failure, and measures to prevent accelerated bone loss are warranted. Hormone therapy (HT) should be provided to eliminate symptoms of estrogen deficiency and help prevent osteopenia, but will not necessarily (and inexplicably) prevent pregnancy in the 5-10% of women who conceive spontaneously after the diagnosis is made. There are no data indicating that these young women are at increased risk of side effects from HT. If pregnancy is desired, use of donor oocytes with in vitro fertilization is most likely to result in pregnancy.

30 years of data: impact of the United States in vitro fertilization data registry on advancing fertility care.

OBJECTIVE: To summarize and assess the impact of key research generated through the Society of Assisted Reproductive Technology (SART)-initiated United States IVF registry and annual reporting system. DESIGN: Review. SETTING: Eligible studies included those that analyzed data generated by the National IVF data collection program (through SART or Centers for Disease Control and Prevention). PATIENT(S): Not applicable. INTERVENTION(S): Not applicable. MAIN OUTCOME MEASURE(S): Summarize and report outcomes of research using National IVF registry data. RESULT(S): The Society of Assisted Reproductive Technology was founded in 1985 and published the first annual US IVF data report 30 years ago in 1988 in Fertility and Sterility. In 1995, the Centers for Disease Control and Prevention subsequently began collecting data from IVF programs and published their first report in 1997. This annual National IVF data collection and reporting is a significant responsibility and effort for IVF programs. Using these data sources, 199 articles have been published by clinicians and researchers from across the country. This research has guided the development of evidence-based assisted reproductive technology (ART) practice guidelines during the past 30 years, which have ultimately led to improved quality and patient care. CONCLUSION(S): Since the first SART National IVF data report publication 30 years ago, SART has achieved its original goals of creating a national IVF registry that successfully assesses clinical effectiveness, quality of care, and safety.

Luteal phase estrogen is decreased in regularly menstruating older women compared with a reference population of younger women.

OBJECTIVE: To compare daily reproductive hormone secretion in regularly menstruating older versus younger women. DESIGN: This was a prospective cohort study. RESULTS: Daily morning urine samples were obtained from 106 women, 28 of whom were aged between 20 and 34 years (mean: 27.8+/-3.7 y) and 78 of whom were aged between 35 and 50 years (mean: 40.3+/-3.7 y). Lower luteal estrone-3-glucuronide levels were seen in the older versus the younger group (82.7 vs 93.5 ng/ml, P=0.035). The pregnanediol-3-glucuronide levels in the older group were lower than those in the younger group throughout the entire cycle. The median length of the follicular phase was shorter in the older versus younger women (13 vs 14.5 d, P=0.005). There was no significant difference in the median luteal phase lengths between groups. CONCLUSIONS: We report the new finding that regularly menstruating older women not only have lower pregnanediol-3-glucuronide levels but also have a significant reduction in luteal phase estrone-3-glucuronide compared with a contemporaneous cohort of younger women. This combined deficit may play a key role during the luteal-follicular transition, potentially affecting follicle recruitment and decreasing fecundity in the subsequent cycle.

Premature ovarian "failure" in the adolescent.

Premature ovarian "failure" (POF) is an enigmatic and heterogeneous disorder characterized by amenorrhea, hypoestrogenism, and hypergonadotropinism that occurs in women under the age of 40 years. The predominant causes are different in the adolescent, and more of these causes are associated with permanent cessation of ovarian function. It would seem that the more common causes of POF in adolescents include cytogenetic abnormalities involving the X chromosome, ovarian dysfunction occurring in association with other autoimmune endocrine disturbances, and chemotherapy and/or radiation therapy given for any of a number of malignancies. Special challenges in the adolescent beyond establishing the diagnosis include counseling the young woman and her family and discussing the possibility of future pregnancy. Lifelong therapy must be addressed as well. Any discussion of POF raises numerous unanswered questions that should be the focus of future research.

Infertility, assisted reproductive technology, and adverse pregnancy outcomes: executive summary of a National Institute of Child Health and Human Development workshop.

The National Institute of Child Health and Human Development held a workshop on September 12-13, 2005, to summarize the risks for adverse pregnancy outcomes after assisted reproductive technology (ART), develop an approach to counseling couples regarding these risks, and establish a research agenda. Although the majority of ART children are normal, there are concerns about the increased risk for adverse pregnancy outcomes. More than 30% of ART pregnancies are twins or higher-order multiple gestations (triplets or greater) and more than one half of all ART neonates are the products of multifetal gestations, with an attendant increase in prematurity complications. Assisted reproductive technology singleton pregnancies also demonstrate increased rates of perinatal complications-small for gestational age infants, preterm delivery, and perinatal mortality-as well as maternal complications, such as preeclampsia, gestational diabetes, placenta previa, placental abruption, and cesarean delivery. Although it is not possible to separate ART-related risks from those secondary to the underlying reproductive pathology, the overall increased frequency of obstetric complications, including preterm birth and small for gestational age neonates, should be discussed with the couple. Significant gaps in knowledge were identified, and the basic science and clinical and epidemiologic research required to address these gaps is outlined.

Baseline anatomical assessment of the uterus and ovaries in infertile women: a systematic review of the evidence on which assessment methods are the safest and most effective in terms of improving fertility outcomes.

BACKGROUND: This review focuses on the initial presentation of women who suspect that they are infertile, and how best to assess the anatomy of their uterus and ovaries in order to investigate the cause of their infertility, and potentially improve desired fertility outcomes. This review was undertaken as part of a World Health Organization initiative to assess the evidence available to address guidance for the diagnosis and treatment of infertility within a global context. Providing access to care for infertile women will help to ease the psycho-social burdens, such as ostracization, intimate partner violence and other negative consequences of being involuntarily childless or unable to become pregnant despite desiring a biological child or children. OBJECTIVE AND RATIONALE: The aim of this paper was to present an evidence base for the diagnostic and prognostic value of various investigations used for detecting uterine and/or ovarian pathology in women presenting at fertility clinics for their initial assessment. SEARCH METHODS: We performed a comprehensive search of relevant studies on 28 August and 10 September 2014. A further search was performed on 6 June 2016 to ensure all possible studies were captured. These strategies were not limited by date or language. The search returned 3968 publications in total; 63 full text articles were retrieved and 10 additional studies were found through hand-searching. After excluding 54, a total of 19 studies were analysed. We extracted and tabulated data on the characteristics, quality and results of each eligible study and combined the findings in a narrative synthesis. Risk of bias was assessed according to article type using tools such as assessment of the methodological quality of systematic reviews, Newcastle Ottawa Scale, Cochrane risk of bias tool, quality assessment tool for diagnostic accuracy studies and quality in prognostic studies. Nineteen studies were selected as being the best evidence available. A narrative synthesis of the data was undertaken. Discussion of the data, and resultant consensus for best practice were accomplished in a consensus expert consultation in Geneva, October 2015. An independent expert review process concerning this work and outcomes was conducted during 2016. OUTCOMES: The draft recommendations presented here apply to infertile women whether or not they are undergoing fertility treatment. Transvaginal ultrasound (TVUS) should be offered to all infertile women with symptoms or signs of anatomic pelvic pathology. TVUS should not be offered routinely to women without symptoms of pelvic pathology. Hysteroscopy should be offered if intrauterine pathology is suspected by TVUS. Hysteroscopy should not be routinely offered to infertile women who have normal TVUS findings. In women who have normal TVUS findings and are undergoing IVF, hysteroscopy does not improve the outcome. Good practice points recommend that providers of fertility care should confirm that all infertile women have a recent pelvic examination, recent cervical screening and well-woman screening in line with local guidelines. Additionally, hystero-contrast salpingography in infertile women does not improve clinical pregnancy rates with expectant management in heterosexual couples and should not be offered as a therapeutic procedure. Most of the findings of this review on diagnosis are based on a low, or very low, quality of evidence, according to GRADE Working Group (grading of recommendations, assessment, development and evaluation) criteria. A low quality grading indicates that further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate, while a very low grade indicates that any estimate of effect is very uncertain. WIDER IMPLICATIONS: This review provides the most reliable evidence available to guide clinicians worldwide in the initial, evidence-based investigation of women with fertility problems in order to undertake the most useful investigation and avoid the burden of unnecessary tests.

Should symptomatic menopausal women be offered hormone therapy?

UNLABELLED: Many physicians remain uncertain about prescribing hormone therapy for symptomatic women at the onset of menopause. The American Society for Reproductive Medicine (ASRM) convened a multidisciplinary group of healthcare providers to discuss the efficacy and risks of hormone therapy for symptomatic women, and to determine whether it would be appropriate to treat women at the onset of menopause who were complaining of menopausal symptoms. MAJOR FINDINGS: Numerous controlled clinical trials consistently demonstrate that hormone therapy, administered via oral, transdermal, or vaginal routes, is the most effective treatment for vasomotor symptoms. Topical vaginal formulations of hormone therapy should be preferred when prescribing solely for the treatment of symptoms of vulvar and vaginal atrophy. Data from the Women's Health Initiative indicate that the overall attributable risk of invasive breast cancer in women receiving estrogen plus progestin was 8 more cases per 10,000 women-years. No increased risk for invasive breast cancer was detected for women who never used hormone therapy in the past or for those receiving estrogen only. Hormone therapy is not effective for the treatment of cardiovascular disease and that the risk of cardiovascular disease with hormone therapy is principally in older women who are considerably postmenopause. CONCLUSIONS: Healthy symptomatic women should be offered the option of hormone therapy for menopausal symptoms. Symptom relief with hormone therapy for many younger women (at the onset of menopause) with menopausal symptoms outweighs the risks and may provide an overall improvement in quality of life. Hormone therapy should be individualized for symptomatic women. This involves tailoring the regimen and dose to individual needs.

Should symptomatic menopausal women be offered hormone therapy?

UNLABELLED: Many physicians remain uncertain about prescribing hormone therapy for symptomatic women at the onset of menopause. The American Society for Reproductive Medicine (ASRM) convened a multidisciplinary group of healthcare providers to discuss the efficacy and risks of hormone therapy for symptomatic women, and to determine whether it would be appropriate to treat women at the onset of menopause who were complaining of menopausal symptoms. MAJOR FINDINGS: Numerous controlled clinical trials consistently demonstrate that hormone therapy, administered via oral, transdermal, or vaginal routes, is the most effective treatment for vasomotor symptoms. Topical vaginal formulations of hormone therapy should be preferred when prescribing solely for the treatment of symptoms of vulvar and vaginal atrophy. Data from the Women's Health Initiative indicate that the overall attributable risk of invasive breast cancer in women receiving estrogen plus progestin was 8 more cases per 10,000 women-years. No increased risk for invasive breast cancer was detected for women who never used hormone therapy in the past or for those receiving estrogen only. Hormone therapy is not effective for the treatment of cardiovascular disease and that the risk of cardiovascular disease with hormone therapy is principally in older women who are considerably postmenopause. CONCLUSIONS: Healthy symptomatic women should be offered the option of hormone therapy for menopausal symptoms. Symptom relief with hormone therapy for many younger women (at the onset of menopause) with menopausal symptoms outweighs the risks and may provide an overall improvement in quality of life. Hormone therapy should be individualized for symptomatic women. This involves tailoring the regimen and dose to individual needs.

Urinary beta-FSH subunit concentrations in perimenopausal and postmenopausal women: a biomarker for ovarian reserve.

OBJECTIVE: The purpose of this study was to develop an integrative assessment of pituitary follicle-stimulating hormone (FSH) secretion and to validate these measurements in a population of perimenopausal (PERI) and postmenopausal (POST) women. DESIGN: In this cross-sectional study, 170 POST and 20 PERI women collected first-void morning urine samples and had a single blood sample drawn on the same day. For comparison, 11 midreproductive-aged women had urine samples collected for one menstrual cycle. In addition, one 48.5-year-old woman collected daily urine samples for 4 consecutive years during her menopausal transition. Urine samples were assayed for estrone glucuronide (E1G) and pregnanediol-3-glucuronide (PdG) and were normalized to creatinine. An ELISA assay was developed for measurement of the free beta-FSH subunit in urine. RESULTS: Mean age (+/- SD) of the PERI and POST women were 48.1 +/- 3.0 and 52.8 +/- 4.1 years, respectively. Mean serum FSH levels were 9.5 +/- 5.8 and 79.3 +/- 32 IU/L (P < 0.001) in the PERI and POST women. Mean urinary beta-FSH/Cr for the PERI were 1.8 +/- 1.2 ng/mg; for the POST, 9.3 +/- 4.5 ng/mg (P < 0.001). Mean estradiol, E1G/Cr, and PdG/Cr levels were also significantly different between the two groups. There was a high correlation between serum FSH and urinary beta-FSH/Cr for the PERI (r = 0.584, P = 0.007) and POST (r = 0.54, P < 0.001), with minimal overlap in the urinary beta-FSH/Cr levels between the PERI and POST groups. A significant correlation between PdG/Cr and urinary beta-FSH/Cr was observed for POST (r = 0.581, P = 0.002). No correlation was seen between urinary beta-FSH/Cr and E1G/Cr or estradiol levels. In the perimenopausal participant, who collected 4 years of daily urine samples, urinary beta-FSH/Cr levels progressively increased during the follicular phase and, by the fourth year, there were persistent, almost tonically high elevations of beta-FSH/Cr in the urine. CONCLUSIONS: Urinary beta-FSH subunit measurements are a useful marker for monitoring ovarian function during the menopausal transition. Urinary free beta-FSH subunit concentrations reflect pituitary FSH secretion and serve as a biomarker for ovarian reserve.

The effect of low-dose conjugated equine estrogens and cyclic MPA on bone density.

OBJECTIVE: to compare the effect of 0.3 and 0.625 mg conjugated equine estrogens on bone mineral density (BMD) in a private practice setting. METHODS: postmenopausal women interested in hormone replacement therapy were prescribed either 0.3 or 0.625 mg conjugated equine estrogens daily with 10 mg medroxyprogesterone acetate days 1-12 of the month. All women were given calcium citrate 1000 mg/day and vitamin D 400 IU/day. DEXA bone mineral density studies of the spine and hip were performed at baseline and 1 year. RESULTS: there was no significant difference in BMD at the spine, the trochanter or the femoral neck compared with baseline in either the 0.625 or 0.3 mg group. The mean percent increase in BMD for the 0.3 versus 0.625 mg group was: spine 2.6 versus 3.8%, femoral neck 1.8 versus 1.5%, and trochanter 0.5 versus 2.6%. CONCLUSION: both the 0.625 mg dose and the 0.3 mg dose of conjugated equine estrogens preserved BMD at the spine and hip over one year in early postmenopausal women who were also given cyclic medroxyprogesterone acetate, calcium citrate and vitamin D.

A short study in the treatment of hot flashes with buccal administration of 17-beta estradiol.

OBJECTIVE: To assess the efficacy and safety of 17-beta estradiol buccal tablets in reducing hot flush frequency (HFF) in postmenopausal women. METHODS: Estradiol buccal tablets containing 0.05, 0.1, 0.2, or 0.4 mg or placebo were administered for 28 days to 99 postmenopausal women in a randomized, double-blind study; 19 premenopausal women were studied concurrently for comparison of laboratory data. Objective and subjective assessments of HFF were obtained along with measures of estradiol, estrone, follicle-stimulating hormone (FSH), and luteinizing hormone (LH). RESULTS: Measurements of HFF revealed significant decreases from baseline in all estradiol groups (P < 0.01). In the 0.4 mg group, HFF decreased significantly compared to placebo (P < 0.01). All estradiol doses produced similar improvement in the vaginal maturation index. Mean serum estradiol levels increased as doses increased but were lower than in the premenopausal subjects. Mean serum FSH and LH levels decreased in all estradiol groups but not to the levels of the premenopausal subjects; the greatest decrease occurred at the two highest estradiol doses. CONCLUSION: A numerical dose-response relationship with hot flushes was seen in this pilot study comparing 0.05, 0.1, 0.2, and 0.4 mg buccal estradiol. Only 0.4 mg 17-beta estradiol significantly reduced the occurrence of hot flushes compared to placebo.

What the American Society for Reproductive Medicine does for you.

The American Society for Reproductive Medicine, one of the older professional medical societies in the United States, is devoted to education, support of research, and advocacy in the field of reproductive medicine. It is also the oldest and largest medical society devoted to reproductive medicine in the world. A multidisciplinary organization, the Society is composed of ∼8000 members from the United States and more than a hundred other countries and undertakes a large number of activities aimed at advancing the discipline of reproductive medicine.