Age and Fertility

Age and Fertility 

Although it is well known that women have a decrease is egg number with aging, many American women are delaying childbearing. Societal shifts focusing on career and education, although wonderful for women, have led to many attempting to conceive at a later age when fertility has decreased. Advances in technology, and celebrities publically having children at a later age, have led to many women not worrying about their fertility potential until it is too late.

But this approach is not smart. As women age, not only do we run out of eggs, but the increase in genetic abnormalities and miscarriage increases. Thus, a delay in conception attempts results in a lower chance of getting pregnant per month and a greater odds of miscarriage if she does conceive. The numbers can sometimes be alarming.

The odds of getting pregnant per menstrual cycle is called fecundability. Many reproductive studies evaluate fecundability as a surrogate marker of fertility (as it is easier to measure a positive pregnancy test than follow a pregnancy out to a live birth). The average fecundability for young women, under the age of 32 years, is approximately 20-25%. Thus, most young couples who try to conceive will get pregnant within 3-4 months. By 1 year of trying at this age, 15% will not be pregnant, thus meeting the definition of infertility. Infertility impacts 1/8 women.

Fecundability markedly decreases with age for women who have never conceived. If you are attempting conception for the first time at age 35, fecundability is 12% per cycle, at age 38 it is 5% per cycle, at age 40 it is 3% per cycle, and fecundability is even lower at age 40 and above. Once you have a child, these numbers are not as scary - 20% at age 33, 15% at age 35, 13% at age 39, and 8% at age 40 (Steiner 2017). This is because women who have never conceived, or never tried to conceive, may have underlying fertility issues that we do not know about. 

What can women do about this?

My thoughts:

1.    When you are ready to conceive, make sure you are making your best effort with each cycle (understand what optimizes natural fertility).

2.    Talk to your regular gynecologist or an infertility specialist about tests of ovarian reserve and what they mean. The most common is an AMH test, it is not perfect, and has not been shown to correlate with fecundability in a non-infertile population, but can help you understand your reproductive timeline.

3.    If you know you do not want to begin having children until after age 32, then consider seeing a reproductive endocrinologist to learn about egg freezing (If this starting age is closer to 35-37 years old and you potentially want more than one child, then this recommendation is even stronger).

Ovarian reserve testing

The most common test to evaluate ovarian reserve is called AMH (antimullerian hormones). AMH is made from cells that surround the small antral follicles inside the ovary (each follicle has an egg).

Women are born with a set number of eggs, which declines with time. Each month, a group of these eggs grow, can be seen on ultrasound, and are called antral follicles. Of the antral follicles, one follicle will grow under the stimulation of follicle stimulating hormone from the brain (FSH), as this follicle grows the egg inside it will mature, and then eventually this follicle ruptures and the egg ovulates. All other antral follicles that month undergo atresia and die. 

AMH does vary each month, correlating with the number of antral follicles. Women will have good months and bad months, although typically neither the antral follicle count (AFC)  nor the AMH value will vary by much. A low AFC or a low AMH value represents concern for diminished ovarian reserve. A woman with diminished ovarian reserve will have fewer eggs reaming than her peers, will enter menopause earlier, and will not have as many eggs available for fertility treatments (if indicated). Many younger women with diminished ovarian modify their reproductive goals in order to suit this new timeline by either earlier attempts at conception or egg freezing.

Egg freezing

An option for women who desire delayed conception until an older age is elective egg freezing. Freezing the eggs at a younger age correlates with improved outcomes when ready for conception. This option provides women with greater reproductive freedom and allows for improved family planning. As technology advances, so does expected outcomes and success rates with egg freezing. The newer freezing technique which is now standard (called oocyte vitrification) has drastically improved egg survival and now made elective egg freezing a possibility. It is important to remember that the effectiveness of egg freezing for older or infertile women has not been proven. The currently quoted success rate is a 4-5% live birth rate per egg frozen/warmed. It is important to understand that age of freezing likely makes a large difference here and that current research is both active and ongoing. Freezing eggs when you are younger improves both the quality and quantity of eggs available. 

Surprisingly, egg freezing is a relatively quick process and usually is completed within 2 weeks. Women take called hormone injections called gonadotropins (mostly synthetic FSH, a normal hormone released from the brain) to stimulate the growth of many eggs at one time. This process is called “controlled ovarian hyperstimulation” and takes, on average, 8-12 days. During this time period, women will be monitored with transvaginal ultrasounds to measure follicular growth and blood work to check both estradiol and progesterone (usually every 2 days or so). As more eggs are stimulated to grow, estradiol levels rise, and as eggs get closer to maturity, progesterone is elevated. These results are used to modify the nightly dose of gonadotropins. Once the highest number of eggs reach maturity, a trigger shot is used to finalize maturity and allow for retrieval. The most invasive part of egg freezing is the egg retrieval. While sedated, a needle guide is attached to a transvaginal ultrasound probe and each follicle is entered and the fluid inside (and the egg) is aspirated into tubes. An embryologist in the lab then inspects this follicular fluid to identify the occytes. All mature eggs are then prepared for freezing. The process of vitrification, where the central liquid of the oocyte is removed, the oocyte is collapsed, and then frozen in liquid nitrogen, appears highly effective for egg freezing.

Importantly, in vitro fertilization (IVF) will be required when it is later time for use. Eggs will be thawed, fertilized with a single sperm, and embryos are created. Embryos then grow out in culture for 5-6 days until they are at the normal stage of implantation and called a blastocyst. Blastocysts can be refrozen, biopsied for preimplantation genetic screening (PGS) and then frozen, or transferred into the uterus. Although some loss is expected in the freeze/thaw process, and rates or survival appear lower for women of older at time of egg freezing, egg freezing expands reproductive options for women.

Many women are unaware that success will always be tied to the age of the egg. Egg quality is better when younger, and so if given the opportunity to freeze your eggs at 30 years versus at 37 years, earlier will always be better. Success rates with fertility treatments are improved at a younger age. Even with IVF, the likelihood of successful ongoing pregnancy is compromised by age. After the age of 30 years, the probability for ongoing pregnancy decreases by about 1.5% per year. In addition, miscarriage rates (largely due to genetic abnormalities) even with IVF cycles increases with age. Miscarriage rates are 15% in women under 35 years, 25% in women at age 40 years, and more than 70% in women over 44 years of age. The take home message as it related to egg freezing: the sooner the better. 

Is egg freezing for you?

As a reproductive endocrinologist, I often see patients concerned about their reproductive potential who desire a family but are not yet ready for motherhood. Personally, I believe that egg freezing is a game changer. Allowing yourself the freedom for greater reproductive flexibility is a beautiful thing. It is important to remember that there are no guarantees, not all women who freeze eggs will have a child born from them. Sometimes the process will not work (for a variety of reasons), but this is placing an investment in you and in your reproductive future.  You are giving yourself the best available option at the family you want and in the timeline you desire. If the timeline is not flexible (I can relate, as mine was not), then at least preserving your fertility at a younger age by freezing your eggs allots you the highest probability for success. Important to note, many women who freeze their eggs will get pregnant naturally without a problem. They may never use these eggs, or they may use them for later children. Regardless, they have been proactive in preserving their fertility, have had decreased anxiety about family building, and granted themselves a slight reprieve from the biological clock.

References:

Steiner AZ and AM Jukic. The impact of female age and nulligravity on fecundity in an older reproductive aged cohort. Fertil Steril 2016;105:1584-8.

Centers for Disease Control and Prevention, American Society for Reproductive Medicine Society for Assisted Reproductive Technology. 2011 assisted reproductive technology: national summary report. Atlanta (GA): CDC; 2013. 

Ziebe S, Loft A, Peterson JH, Anderson AG, Lindenberg S, Peterson K, et al. Embryo quality and developmental potential is compromised by age. Acta Obstat Gynecol Scand 2001;80:169-74.

Cil AP, Bang K, Oktay K. Age specific probability of live birth with oocyte cryopreservation: an individual patient data meta-analysis. Fertil Steril 2013;100:492-9.