Rani Fritz, D.O., Ph.D., Joel Batzofin, M.D.
New York Fertility Services
New York, NY
In the U.S., over the past several decades spanning from 1970-2014, there has been a dramatic rise in the age of first time mothers from 21.4 to 26.3 years old (1, 2), and a dramatic rise in woman having children for the first time aged 35-44 years old (3). These trends are consistent with many other developed countries. The average age of first time mothers in the European Union is just under 29 years old, with one of the highest average age of first time mothers seen in Italy at 30.6 years old (4).
Delayed motherhood and decreasing birthrate may have adverse societal and economic impacts as well as increase the risk of maternal and neonatal complications. From a societal standpoint, it has been estimated that a fall below the replacement level of approximately 2.1 live births per woman can adversely affect the ability to care for the growing elderly population and sustain the economy (5). From a health care standpoint, delayed motherhood and pregnancy at “advanced maternal age”, significantly increases almost all serious maternal and neonatal complications (6). Additionally, delaying childbearing increases the risks of remaining involuntarily childless, which can negatively impact mental health and physical well-being (7). Despite these well established facts, relatively little emphasis is placed on counseling reproductive aged women on reproductive aging (RA) and elective fertility preservation (EFP).
It is well documented with multiple historical epidemiological studies that fecundity starts taking a steep decline at ages 35-37 years old (8). Perhaps, the most well studied and frequently referenced epidemiological study was that of the Hutterites (9). The Hutterites immigrated from Switzerland in the late 19th century, settled in the Dakotas and Montana, and were a relatively fertile population with only 2.4% suffering form infertility and an average of 9.6 children per woman. In this cohort, 1 in 10 women stopped reproducing by 35 years of age, 1 in 3 by 40 years of age, and 7 in 8 by 45 years of age. A recent time to pregnancy study with a more heterogenous population revealed similar results (10). This study evaluating 960 women attempting to conceive 3 months or shorter revealed stable pregnancy rates of 82-88% after 12 menstrual cycles in women aged 30-35 years old, decreasing to 71%-76% in women aged 36- 39 years old, and decreasing further to 48%-54% in women aged 40-44 years old. These patients were not followed to live birth and with the known dramatic rise of miscarriages that occurs as women approach and enter their 5th decade of life, it is possible that the discrepancies in fecundity would have widened further if followed to live births. A potential limitation of cohort studies evaluating fecundity with age is that they do not account for a potential decrease in sexual activity that occurs as women age or pathology they may acquire that adversely affect fertility. A study controlling for both of these factors evaluated pregnancy rates after IUI in women with a normal female fertility workup using donor sperm for male factor infertility (11). This study revealed a similar significant decline in fertility after 35 years old with pregnancy rates of 74.1% after 12 cycles of IUI in women aged 26-30 years old and decreasing to 53.6% in women over 35 years old. As above, this study did not follow patients to live birth and the discrepancy may have widened if followed to live birth.
Despite these well-documented facts, studies from many countries reveal that reproductive aged men and women have suboptimal knowledge relating to the effects of RA and the availability of EFP. For example, a large international study evaluating fertility related knowledge amongst over 10,000 men and women from 79 countries trying to conceive demonstrated suboptimal knowledge with an average score of 56.3% on a basic knowledge fertility questionnaire (12). This lack of knowledge may be related to suboptimal counseling from Obstetrician and Gynecologists (OB/GYN), as a survey evaluating 183 women that underwent elective oocyte cryopreservation (EOC) revealed that only 25% learned about it from their OB/GYN (13). Additionally, a study evaluating OB/GYN residents revealed that although 82.9% believed that patients should be counseled on RA, their knowledge relating to the subjects were suboptimal with 47.4% overestimating the age at which a significant decline in fertility begins to occur and 78.4% overestimating the success of IVF (14). Indeed, a recent study conducted alongside the research division of the American College of Obstetrics and Gynecology evaluating 786 post-residency OB/GYN’s experience and knowledge relating to counseling patients on RA and EFP revealed that although a significant majority favored counseling patients on these subjects, in reality, far fewer did, with the most frequently cited reasons being lack of time and self-reported limited knowledge (15).
In over a decade spanning from 2006-2015 the percentage of IVF cycles has increased 40.4% (16), and the percentage of cycles in women aged ≥ 41 years old has increased 46.4%, however live birth success rates per cycle initiated using autologous oocytes in this age group has not improved much with success rates of 3.2% in women 42-44 years old, and only 0.8% in women > 44 years old (16). Following removal of the “experimental” label of oocyte cryopreservation (OC) by ASRM in 2012, OC for fertility preservation has increased 30.6% from 6123 cycles in 2014 to 8825 cycles in 2016 (17). Given these facts, it is imperative to increase awareness related to RA and the availability of EFP amongst reproductive aged women who desire children past their reproductive peak. The need for this type of counseling is apparent through a unique Fertility Counseling and Assessment clinic in Denmark with one of its purposes being to provide pro-fertility counseling to reproductive aged men and women (18). A survey of women presenting to this clinic revealed that 99% found it helpful, 70% wanted to know how long they can safely prolong their childbearing, and following counseling, 35% stated that they would advance the decision to become pregnant (18).
As Reproductive Endocrinologists, our knowledge relating to RA and EFP is on the forefront, however, we must not take for granted that general OB/GYN physicians and other primary care physicians have similar knowledge. An important aspect of our field is to educate general OB/GYN’s and other primary care physicians on RA and the availability of EFP as they are often in an ideal position to counsel reproductive aged women on these important topics. Particular attention must be given to screen for patients at increased risk for premature ovarian failure including history of chemotherapy or pelvic radiation, severe endometriosis, history of ovarian surgery, strong smoking history, Fragile X pre-mutation, and strong family history of early menopause, as these patients could benefit most from counseling on RA and OC (19). Additionally, consideration must be given to embrace OC for elective reasons. Although ASRM has removed the experimental label for OC, they do not endorse its use for elective reasons, stating “Data on the safety, efficacy, cost-effectiveness, and emotional risks of EOC are insufficient to recommend EOC”(20). Although long-term data are lacking, short term safety data relating to children born from cryopreserved oocytes are reassuring indicating that those born from OC are not at increased risk for adverse obstetrical or neonatal outcomes compared to those born from freshly inseminated oocytes, and are not at increased risk for congenital anomalies compared to the general population (21, 22). Additionally, embryos derived from insemination of cryopreserved oocytes are not at increased risk for aneuploidy compared to embryos derived from insemination of fresh oocytes (23). In regards to efficacy, available data thus far has been reassuring. Data, including randomized controlled studies, have revealed that pregnancy and live births rates are comparable between insemination of cryopreservered and fresh oocytes (24, 25). As with IVF success rates using insemination of fresh oocytes, success rates of EOC largely depend on age at which EOC was performed. A large series of patients that underwent EOC and subsequently oocyte thaw with insemination and transfer of resultant embryos revealed that women that underwent EOC ≤ 35 years old had 50% live birth rate, whereas, women that underwent EOC ≥ 36 years old had a 22.9% live birth rate (26). Although EOC is generally not covered by insurances, from a financial standpoint, it may be cost-effective in those that desire pregnancy past their reproductive peak. Two mathematical models suggest that EOC may be cost effective if performed at age 35 years old in women that will attempt to get pregnant ≥ 40 years old (27, 28) . There is little data on the emotional risks of EOC, however, a recent survey using a validated decision regret scale of women that underwent EOC revealed that slightly less than half of responders had some form of regret, with the majority of those stating mild regret (29). Despite reporting regret, 89% of those surveyed stated that they would be happy they froze their eggs even if they never returned to use them. Methods to minimize regret may include improved counseling sessions and undergoing EOC at younger ages in order to maximize outcomes and number of eggs frozen. In addition to the potential of decision regret, women contemplating EOC should also be extensively counseled on other potential drawbacks of EOC. One potential drawback is not returning to use their cryopreserved oocytes. At time of their publications, several studies revealed that approximately 6% - 9.3% of women returned to use their oocytes, with the largest series of 1468 patients undergoing EOC reported that 9.3% returned to use their oocytes (13, 26, 30). Decision of how many oocytes to cryopreserve, and therefore, how many cycles of controlled ovarian hyperstimulation to undergo, may be guided by the use of a recent mathematical model revealing the number of mature oocytes needed to be cryopreserved in order to achieve at least 1 live birth (31). This model highlights the importance of age at which patients undergo EOC. To achieve a 75% chance of at least 1 live birth, a 34 year old a woman will need to freeze 10 mature oocytes, increasing 20 mature oocytes at 37 years old, and 61 mature oocytes at 42 years old. Of course, patients must be counseled that oocyte cryopreservation, even at younger ages, and regardless of how many mature oocytes are frozen, does not guarantee a live birth and there is always a possibility of failure.
The importance of counseling patients on RA should not rely on endorsing EOC, but more importantly on counseling on the effects of RA related to fecundity, pregnancy complications, and outcomes. Of course, EOC, should be part of the discussion and those interested should undergo a thorough counseling session with a trained provider incorporating the important points above. Although counseling on RA should be offered to all women desiring childbearing past their reproductive peak, particular care should be taken during a history and physical to screen for women at risk for an accelerated decline in their reproductive potential. Our society has come a long way in terms of increasing women’s reproductive autonomy, however, an integral and often forgotten component of women’s reproductive autonomy is adequate counseling on the effects of RA. Empowering women with information and adequate counseling sessions related to RA will enable them to maximize and make informed decisions relating to their reproductive potential.
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