The age at first birth is ever increasing. In Europe, women aged 35 years or older accounted for 22.5% of all live births in 2013, compared with 17.7% in 20041. It is a well-documented reality that both women and men are less eager to procreate while young. Responsible factors include societal changes, the grip of work, career and technology, and the social media selling the dream of postponing motherhood “until the time is right.” Yet, the impact of age on reproductive ability places women at a disadvantage due to the finite number of oocytes and their continuous alterations in DNA integrity as female age advances.
The natural decline in female reproductive potential over time has 2 main etiologies: depletion of the number of oocytes in the ovary and a decrease in oocyte quality. Anti-Müllerian hormone, a glycoprotein hormone secreted by the granulosa cells of preantral and antral ovarian follicles, peaks in the early 20s, and gradually declines until the menopause2. It is commonly used as a biomarker of a woman’s ovarian reserve, along with levels of follicle-stimulating hormone and antral follicular count. Diminished ovarian reserve due to increased maternal age is a common reason for failure to spontaneously conceive, but the effects of advanced maternal age are becoming evident during assisted reproductive technology (ART) therapy. As women are born with a finite number of oocytes, progressive reduction in the ovarian follicular pool means that older women have fewer eggs of diminished quality and increased susceptibility to chromosomal and meiotic abnormalities.
Couples delaying family plans should be aware of the risk of not having any or less children than desired. While large population studies on this topic are lacking, theoretical calculations make sober reading. In a 10,000 couple simulation study, Habbema et al showed that without planning to avail of in vitro fertilization (IVF), couples should start no later than age 32 years for a 1-child family, at 27 years for a 2-child family, and at 23 years for 3 children3. Even when IVF is an option, couples desiring only 1 child should start trying to conceive when the female partner is 35 years of age or younger, for 2 children, the latest starting age is 31 years, and for 3 children 28 years.
The risks of pregnancy for a 25-year-old female are very different compared with age 45, advanced maternal age alone being a well-established risk factor for pregnancy-associated complications for both mother and baby4. Cleary-Goldman et al,5 analyzed the obstetrical outcome of pregnancies in 3 groups (younger than 35 y old, 35–39, and over 40), in total 36,056 women that conceived spontaneously. Increasing age was significantly associated with miscarriage [adjusted odds ratio (adjOR), 2.0 and 2.4 for ages 35–39 y and age 40 y and older, respectively), chromosomal abnormalities (adjOR, 4.0 and 9.9), congenital anomalies (adjOR, 1.4 and 1.7), gestational diabetes (adjOR, 1.8 and 2.4), placenta praevia (adjOR, 1.8 and 2.8), and cesarean delivery (adjOR, 1.6 and 2.0). Patients aged 35–39 years were at increased risk for macrosomia (adjOR, 1.4). Increased risk for abruption (adjOR, 2.3), preterm delivery (adjOR, 1.4), low birth weight (adjOR, 1.6), and perinatal mortality (adjOR, 2.2) was also noted in women aged 40 years and older.
There is scanty literature on the maternal and newborn risks associated with female age in a population that conceived following IVF. Studies show women receiving ART are more likely to be older, and thus more likely to exhibit co-morbidities such as renal and cardiovascular disease than the younger cohort4,6,7.
IVF in the aging female
Education aside, little can be done in relation to when a couple decides to start a family. With increasing maternal age, the likelihood of a pregnancy establishing decreases and many women will require fertility investigations and treatments. The rate of ART cycles carried out in the United States increased by 32%, from 138,198 cycles in 2006 to 182,154 in 2015, and the number of live births increased from 54,656 to 71,169 in the same period6. The age profile of women attending for ART is constantly changing, 38% of ART cycles carried out in the United States in 2015 were among women aged between 18 and 34 years. The largest cohort of women receiving ART treatments were those between 35 and 40 years, with usage declining after the age of 40. Indeed, 16% of cycles were carried out among women age 41–44, and only 5% among those age 45 and above6.
By comparison, research carried out in the United Kingdom in 2014 shows that the largest cohort receiving IVF treatments were women between 18 and 34, accounting for 43.4% of all cycles compared with 37% of those between 35 and 40. Women age 45 and above accounted for just 2% of IVF cycles carried out in 20147. The average age of a woman receiving treatment in the United Kingdom was 35 years, compared with 36 years in the United States, highlighting similar trends globally6,7.
Increased oocyte aneuploidy
The success of ART treatments and the likelihood of a pregnancy establishing and progressing depends on the quality of oocytes and sperm. Female age has a significant effect on the expression of genes regulating the oocyte cell cycle (eg, chromatin assembly and M-phase of meiosis)8. As a result, oocytes of older women are less resistant to meiotic errors and chromosomal abnormalities, leading to higher rates of embryonic and fetal anomalies with lower rates of pregnancy and higher pregnancy losses4,8.
Increased embryonic aneuploidy
The age-related impairment of embryo competence is closely associated with aneuploidy in human embryos, which arises predominantly from miss-segregation in meiosis. Rates of 3PN zygotes are increased with maternal age in both IVF and ICSI treatments8. Embryo assessment through PGD shows that aneuploid rates in day 5 embryos are 31.7% in younger than 35 years old, 44.2% at 35–37years old, 43.1% at 38–40 years old, 76.3% at 41–42 years old, and 84.8% after 42 years old9. These increased rates of chromosomal abnormalities in women of advancing age, lead to higher incidence of spontaneous miscarriage, Harton and colleagues recording rates of 13% in younger than 35 years old, 17.9% among 35–37 years old, 26% for 38–40 years old, 38.1% in 41–42 years old, and 52.7% in women older than 42 years old.
Decreasing rates of IVF pregnancy with increased maternal age
The number of oocytes retrieved after IVF decreases with age, with an average of 10 eggs retrieved from those between 25 and 29 years, compared with 7 for those from 40 to 46 years6–8. As regards IVF success rates, 40% of women between 25 and 29 years achieve a positive β-hCG test following IVF, compared with 32% of those between 35 and 39 years and 17% of those age 40–46 years8. Reaching the stage of a detectable clinical intrauterine pregnancy is less likely as female age increases: 33% for women between 25 and 29 years, 31% for those age 30–34 years, 26% for those age 35–39 years, and just 12% for those 40–46 years6. Live birth rates also decline with age: 30% of IVF cycles in women age 35 result in delivery of a liveborn infant, compared with 15% in those age 40, and 1% in those age 456.
As regards female age impact, rates of embryo transfer, pregnancy and live birth decline as a woman’s age increases, while rates of miscarriage, intrauterine death, and adverse obstetric outcomes steadily rise4,6,7.
Reproductive reality conflicts with the high expectations of many patients attending for IVF, particularly at advanced female age. Detailed counselling is paramount before advising and pursuing IVF therapy. Table 1 present some clinical points that could be of value to both practitioners and patients.
Women above 35 years of age are a growing segment of patients attending for fertility services like IVF. Open discussion about the limitations of ART therapy at advanced female age, risks of pregnancy for the mother and child ensure that couples are fully informed and have realistic expectation before pursuing emotionally and financially exhaustive interventions.
Preventive education to include the importance of establishing a family early in the female adulthood should be considered by health policy makers. Institutions educating young adults should equally provide contraceptive and fertility advice under one umbrella of female and male reproductive health. Similarly, society at large should facilitate young couples desiring a family and provide both support for new mothers and father and also equal opportunities for female career progression. This minimal investment will be far more beneficial to society than the burden of fertility-related stress, loss of productivity, and ART related complications to include prematurity, maternal morbidity and neonatal costs associated with advanced female age.
Conflict of interest statement
The authors declare that they have no financial conflict of interest with regard to the content of this report.
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