‍

As society continues to evolve, so do family dynamics. One notable shift is the trend toward delaying parenthood, with many choosing to become parents at an older age. While there are benefits to having children later in life, it remains crucial to acknowledge and understand the potential risks that come with advancing maternal and paternal age.

Maternal age

Whether using your own (fresh or frozen) or donor eggs, the age of the egg source is the key determining factor for the risk of chromosomal abnormalities ("aneuploidy"). Differences in the number of chromosomes, such as Down Syndrome (an extra copy of chromosome 21), typically occur by random chance at conception. Since they're rarely inherited, they can happen in any conception, however, they become more likely as the age of the egg source increases. Because these chromosomal differences have a significant impact on the success of a pregnancy and the health of the resulting pregnancy, counting the number of chromosomes in an embryo via PGT-A can provide valuable information during embryo screening

The Biology

Most cells in the body have 46 chromosomes (organized in pairs), but eggs and sperm each have only 23. This way, when they combine, they create a cell with 46 chromosomes for the embryo to develop from. This means that when the eggs and sperm are being created, these pairs need to split up. If an egg or sperm has an extra or missing chromosome, the embryo can end up with too much or too little genetic material.

In males, chromosome splitting happens continuously after puberty. But in females, this splitting process starts before birth, pauses, and only finishes right before ovulation. The longer this pause, the harder it is for the chromosomes to split correctly, which is why older eggs have a higher chance of chromosomal differences.

The number of eggs retrieved through the IVF process—and thus available for fertilization—depends heavily on individual factors. Generally, however, this number decreases as the egg source's age increases.

Paternal age

An association between advancing paternal age (APA) and new, or de novo, genetic mutations was first noted in the 1970s with autosomal dominant conditions that affect the musculoskeletal system, such as Achondroplasia  (characterized by dwarfism and abnormal bone growth), Apert Syndrome (affects the development of the skull, face, and limbs), and Marfan Syndrome (affects the body's connective tissue, leading to various skeletal and cardiovascular abnormalities). These new genetic changes can contribute to a variety of developmental and physical disabilities in offspring, and since they're not inherited, have previously been impossible to detect on standard PGT.

The biology

As men age, their sperm quality and quantity may gradually decline. This decline in sperm health is attributed to various factors, including increased DNA mutations and alterations in epigenetic marks. Advanced paternal age has been linked to a higher likelihood of new genetic mutations in offspring, which could lead to an elevated risk of certain conditions, such as autism, schizophrenia, and rare genetic disorders. Unlike maternal age related risks, there is less data associating specific age ranges with absolute risks and the definition of APA may vary, but research has yielded the following risk estimates.

Advanced paternal age has also been associated with decreased semen quality, live birth rates and pregnancy complications.

• A review of research spanning two decades revealed a decline in semen volume (3%-22%), sperm motility (3%-37%), and the percentage of normal sperm (4%-18%) when comparing 30-year-old men to those aged 50. Comparing this same group and controlling for female age, found a decrease in pregnancy rates ranging from 23% to 38% .
• An retrospective analysis from 4057 first cycles at fertility centers between 2009 and 2013 revealed a statistically significant correlation between increasing paternal age and reduced chances of viable pregnancy and live birth. This relationship resulted in a 10% decrease in the likelihood of pregnancy in women aged 35 when their male partner was older than 40 years, in comparison to partners under 30 years of age.
• A systematic review and meta-analysis from 2020 revealed that compared to fathers <20 years of age, fathers over 40 were associated with higher risks of cardiovascular abnormalities, facial deformities, urogenital abnormalities, and chromosome disorders in their offspring.

• There are reported associations with advancing paternal age and birth defects. Single gene disorders that are more common in older dads are typically associated with birth defects. As a result, at least part of the increased risk of birth defects associated with paternal age can be attributed to these single gene mutations.

How Orchid can help

Pre-implantation genetic testing (PGT) offers a way of screening embryos for the risks discussed above to provide prospective parents additional peace of mind. The first step of any embryo screening is to assess the number of chromosomes via PGT-A. It is important to remember that every cycle is expected to have chromosomally abnormal (or aneuploid) embryos, however, the proportion is expected to be higher for older egg sources. Orchid not only addresses common aneuploidies associated with advancing maternal age, but is the only PGT capable of detecting certain chromosomal conditions such as triple X triploidy, molar embryos, and targeted microduplications/delections, which may be associated with adverse outcomes.

Previously, there have been very few options for families concerned about the risks associated with advancing paternal age as embryo screening was unable to detect new mutations that weren't inherited from a parent. Orchid is the only embryo screening available that can screen for de novo mutations that are more common in the offspring of older fathers and may be associated with neurodevelopmental disorders and/or birth defects. Orchid's whole genome preimplantation genetic testing (PGT-WGS) screens for hundreds of such disorders while also providing genetic predisposition screening for complex conditions such as schizophrenia and bipolar disorder.

Takeaway

While these risks exist, it's important to note that advancing parental age doesn't guarantee that a child will face these challenges. Many children born to older parents are healthy and thriving. However, being aware of these potential risks allows individuals to make informed decisions about their family planning. 

References

1. Guzzo KB, Hayford SR. Pathways to Parenthood in Social and Family Context: Decade in Review, 2020. J Marriage Fam. 2020 Feb;82(1):117-144. doi: 10.1111/jomf.12618. Epub 2020 Jan 5. PMID: 34012172; PMCID: PMC8130890.
2. Jia CW, Wang L, Lan YL, Song R, Zhou LY, Yu L, Yang Y, Liang Y, Li Y, Ma YM, Wang SY. Aneuploidy in Early Miscarriage and its Related Factors. Chin Med J (Engl). 2015 Oct 20;128(20):2772-6. doi: 10.4103/0366-6999.167352. PMID: 26481744; PMCID: PMC4736891.
3. Sanders KD, Silvestri G, Gordon T, Griffin DK. Analysis of IVF live birth outcomes with and without preimplantation genetic testing for aneuploidy (PGT-A): UK Human Fertilisation and Embryology Authority data collection 2016-2018. J Assist Reprod Genet. 2021 Dec;38(12):3277-3285. doi: 10.1007/s10815-021-02349-0. Epub 2021 Nov 12. PMID: 34766235; PMCID: PMC8666405.
4. Yatsenko, A. N., & Turek, P. J. (2018). Reproductive genetics and the aging male. Journal of assisted reproduction and genetics, 35(6), 933–941. https://doi.org/10.1007/s10815-018-1148-y
5. Reichenberg, A., Gross, R., Weiser, M., Bresnahan, M., Silverman, J., Harlap, S., Rabinowitz, J., Shulman, C., Malaspina, D., Lubin, G., Knobler, H. Y., Davidson, M., & Susser, E. (2006). Advancing paternal age and autism. Archives of general psychiatry, 63(9), 1026–1032. https://doi.org/10.1001/archpsyc.63.9.1026
6. Sipos, A., Rasmussen, F., Harrison, G., Tynelius, P., Lewis, G., Leon, D. A., & Gunnell, D. (2004). Paternal age and schizophrenia: a population based cohort study. BMJ (Clinical research ed.), 329(7474), 1070. https://doi.org/10.1136/bmj.38243.672396.55
7. Frans EM, Sandin S, Reichenberg A, Lichtenstein P, Långström N, Hultman CM. Advancing Paternal Age and Bipolar Disorder. Arch Gen Psychiatry. 2008;65(9):1034–1040. doi:10.1001/archpsyc.65.9.1034
8. Kidd SA, Eskenazi B, Wyrobek AJ. Effects of male age on semen quality and fertility: a review of the literature. Fertil Steril. 2001 Feb;75(2):237-48. doi: 10.1016/s0015-0282(00)01679-4. PMID: 11172821.
9. McPherson, N. O., Zander-Fox, D., Vincent, A. D., & Lane, M. (2018). Combined advanced parental age has an additive negative effect on live birth rates-data from 4057 first IVF/ICSI cycles. Journal of assisted reproduction and genetics, 35(2), 279–287. https://doi.org/10.1007/s10815-017-1054-8
10. Fang, Y., Wang, Y., Peng, M., Xu, J., Fan, Z., Liu, C., Zhao, K., & Zhang, H. (2020). Effect of paternal age on offspring birth defects: a systematic review and meta-analysis. Aging, 12(24), 25373–25394. https://doi.org/10.18632/aging.104141
11. THE RATE OF ANEUPLOIDY AND CHANCE OF HAVING AT LEAST ONE EUPLOID TESTED EMBRYO PER IVF CYCLE IN 21,493 PREIMPLANTATION GENETIC SCREENING FOR ANEUPLOIDY (PGT-A) TESTED EMBRYOS AS DETERMINED BY A LARGE GENETIC LABORATORY Morris, Joshua et al. Fertility and Sterility, Volume 116, Issue 1, e15

‍