Should we be happy or worried about the birth of a father at an advanced age?

The sperm is old, can it still be used?

Written by | Alalei (Master of Internal Medicine, Tongji University School of Medicine), Xiaorui (PhD in Obstetrics and Gynecology, Shanghai Jiao Tong University School of Medicine)

Due to social, economic, work pressure, higher education and other factors, couples are getting married and having children later and later. In recent years, my country has gradually relaxed the family planning policy, and more and more men are willing to have two or three children. As we all know, as women age, their fertility gradually decreases. However, the impact of age on male fertility seems to receive less attention. In our tradition, men often have the idea of ​​"establishing a career first, then starting a family", and often use some celebrity examples: the gambling king gave birth to a daughter at the age of 78, Qi Baishi had a son at the age of 79... Whether or not a woman can have a child seems to depend mainly on the woman's factors.

Stanley Ho and his youngest daughter, Pansy Ho | Source: Internet

Is this really the case?

Is there really no upper limit to men’s reproductive age?

Men are fertile throughout their lives—in theory

"In theory"!

Everything starts with the occurrence of sperm. Sperm comes from the testicles, strictly speaking, from the seminiferous tubules of the testicles. Spermatogenesis begins with the differentiation of stem cells. The "stem" in stem cell means "origin", that is, "origin cell", which has unlimited self-renewal and differentiation potential. The spermatogenesis process can be simply summarized as: stem cell → spermatogonia → primary spermatocytes → secondary spermatocytes → spermatids → sperm. Only when the overall number of spermatogonia decreases significantly will stem cells enter the differentiation stage. Male spermatogenesis continues after sexual maturity until the death of the individual.

Does sperm quality change with age, especially after 50 years of age? There is a lack of representative data on testicular histology and semen quality, and the existing data are inconsistent, so it is difficult to give a satisfactory answer.

In terms of histology, no general shrinkage of testicular volume has been found in the elderly. In terms of semen quality, due to the different characteristics of the populations included in each study, there are differences in the results of indicators such as sperm motility, sperm concentration, and sperm count. Some studies have shown that there is no significant difference between elderly people over 60 years old who have given birth and younger fathers in various indicators (such as testosterone levels, sperm count, etc.); other studies have shown that in people aged 25 to 50, sperm concentration gradually decreases with age [1]. In general, compared with women during menopause, men's reproductive function will not be lost suddenly. In theory, men have the ability to reproduce throughout their lives.

Why say “theoretically”?

The process of spermatogenesis is affected by many factors, including underlying diseases (e.g., chronic renal/liver dysfunction, diabetes, etc.), endocrine levels, ionizing radiation, drugs, heavy metals, smoking, diet, drinking, etc., and is also related to idiopathic factors. The previous ones are easy to understand. What is "idiopathic factors"? It means that the sperm quality in the population has undergone systematic changes. According to previous studies, when the sperm concentration is less than 30~55×106/ml, fertility begins to decline. However, many studies in the past 15 years have reported that the median sperm concentration of young men (18~21 years old) is 41~55×106/ml, which means that a considerable proportion of men have poor semen quality, and this general downward trend has continued for decades [2]. Even when the World Health Organization (WHO) updated the manual for laboratory testing of human semen [3], some semen quality indicators were lowered.

Update of WHO semen quality indicators[3] (click to see larger image)

The data from China is not optimistic either. During a 15-year observation period (2001-2015), researchers evaluated the sperm quality of 30,636 young men (average age 21.6 years old). The results showed that the sperm concentration decreased from 68×106/ml to 47×106/ml, the proportion of normal morphology decreased from 31.8% to 10.8%, and the proportion of qualified donors decreased from 55.8% to 17.8% [4].

In addition, many male diseases that have nothing to do with sperm production itself can also affect the success rate of conception. For example, vas deferens disease, erectile dysfunction (ED), ejaculation disorders, etc. When it comes to infertility, people will naturally focus on the female partner first. In fact, although the data on the causes of infertility vary from region to region, in general, about 1/3 of the cases are purely female, about 1/3 are purely male, and about 1/3 are caused by both male and female problems.

No disease

No bad living habits

Does it mean that having a child in old age is not difficult?

But, having a baby,

I also hope to have a healthy baby!

Let’s first look at a set of data.

First, there is a meta-analysis published in 2020 by Human Reproduction Update, an authoritative journal in the field of obstetrics and gynecology. It is well known that older women will have an adverse effect on fertility, and the results of this analysis show that older men are also associated with an increased risk of spontaneous abortion. The risk of miscarriage increased by 4%, 15%, 23% and 43% in the age groups of 30-34 years old, 35-39 years old, 40-44 years old, and ≥45 years old, respectively. Compared with women, the impact of increasing age on men may not be as obvious, but it also needs to be taken seriously. [5]

Second, the birth of a child is a happy event for the whole family. However, the British Medical Journal (BMJ), one of the four most famous medical journals in the world, has released a set of figures. Scientists analyzed the data of 40,529,905 newborns and their parents born in the United States from 2007 to 2016. After excluding many influencing factors of the mother, they found that if the father is over 45 years old, the probability of premature birth will increase by 14%, the probability of epilepsy in the child will increase by 18%, the incidence of low birth weight in the newborn will increase by 14.5%, the probability of the child entering the intensive care unit will increase by 15.1%, the probability of needing mechanical ventilation will increase by 8.6%, and the probability of other complications will increase by 12.2%. [6]

Third, in real life, if a child has problems during growth and development, people will first look to the mother. However, we must know that the father's sperm also contributes half to the fertilized egg, and we cannot put all the blame on the mother. For example, autism is a representative disease of pervasive developmental disorder. A study conducted a retrospective analysis of 132,271 children and found that the incidence of autism in offspring of fathers over 40 years old was 5.75 times that of fathers under 30 years old [7]. Another study, after analyzing 14,231 children with autism and 56,924 healthy children, also found that the risk of autism in offspring born to men over 40 years old was 3.3 times that of men aged 20 [8]. In addition to autism, there are also many reports that men who give birth at an advanced age are at increased risk of schizophrenia, affective disorders, leukemia, central nervous system diseases, etc. in their offspring.

Wait a moment

Isn’t it said that men have the ability to reproduce “all their lives”?

Even if the sperm count and concentration decreases

That is the change of "quantity"

Why do the adverse effects mentioned above occur?

That’s right, in addition to quantitative changes, there will also be qualitative changes!

Let’s focus on talking about genes!

Genes are the genetic code of an individual, and chromosomes are the carriers of genes. Genetic abnormalities will increase the risk of infertility, fetal arrest, miscarriage, and birth defects. Among the causes of infertility in older women, aneuploidy (i.e. abnormal number of chromosomes) is one of the important reasons. What is "aneuploidy"? Sperm or eggs have 23 chromosomes, represented by n; embryonic cells have 46 chromosomes, represented by 2n, which is an integer multiple. "Aneuploidy" refers to an increase or decrease in the number of chromosomes in a cell by 1 or more. For example, if a certain chromosome is missing one, it is called a haploidy (2n-1); if a certain chromosome is extra one, it is called a trisomy (2n+1). (For details, see "Is it dangerous to have a baby? Afraid that the baby is unhealthy? Is it advisable to freeze eggs? Solving the fertility problems of "older" women")

Similar to eggs, sperm can also be aneuploid. The main reason for aneuploidy is that chromosomes do not separate correctly during meiosis. Data show that the incidence of aneuploid sperm is 5% to 7%; there is still a lack of high-quality research on the relationship between age and the incidence of aneuploidy, and the existing research results are not consistent.

In spontaneous abortion and congenital defects, aneuploidy can come from the father, the mother, or the first few divisions of the fertilized egg. With the progress of human genome engineering, existing studies have found that, except for a few types of chromosomal abnormalities, 84% to 100% of common aneuploidy abnormalities come from abnormalities in the number of chromosomes in the egg, and only 0 to 7.7% come from sperm[9]. Therefore, compared with women, aneuploid sperm in men poses less risk to offspring.

In the past, routine tests on sperm quality mainly included semen volume, sperm count, sperm density, normal morphology, etc. In recent years, sperm DNA fragmentation (SDF) has become a new indicator for evaluating semen quality. SDF refers to the situation where single-strand or double-strand breaks in sperm nuclear DNA or mitochondrial DNA occur due to various reasons, resulting in damage to the integrity of paternal genes. The specific mechanism causing SDF is still unclear. At present, there are three main theories: sperm maturation disorder (Note: the ability of sperm to repair its own DNA and adapt to the environment is reduced), abnormal sperm apoptosis (Note: cells escape the normal apoptosis pathway in some way, and produce abnormal sperm) and oxidative stress (Note: the influence of exogenous and endogenous reactive oxygen species).

There is also an increasing amount of research on the impact of sperm fragmentation rate (DFI, DNA fragmentation index) on male fertility. Here are a few examples.

1. DFI and male infertility. Studies have shown that in normal semen, the DFI is 13.0±7.3%; in the semen of infertile men, the DFI reaches 40.9±14.3%[10]. In addition, DFI is negatively correlated with conventional semen examination indicators (sperm count, sperm morphology, sperm forward motility)[11]. In other words, the higher the DFI value, the worse the conventional semen examination indicators.

2. DFI and recurrent miscarriage. A domestic study showed that 37.5% of husbands of women with a history of recurrent miscarriage had a sperm DFI greater than 30%, while only 25.8% of husbands of women with normal fertility rates had this condition. [12]

3. DFI and embryo development and offspring health. For naturally fertilized embryos, higher DFI may lead to genetic instability of the embryo and increase the risk of genetic or congenital diseases in the offspring; for embryos cultivated by assisted reproductive technology, it may also reduce the success rate of transplantation.

The relationship between age and DFI has been confirmed by many studies. Foreign studies have shown that the sperm DFI level of men over 45 years old is 32.0%, while that of men 30 years old and below is 15.2%, which is twice that of the former. After the age of 40, the sperm DFI level increases rapidly, and the sperm DFI of men aged 30-35, 35-40, and 40-45 are 19.4%, 20.1%, and 26.4%, respectively. [13] Domestic research results are basically consistent with the trend of foreign countries. The DFI of men under 35 years old, 35-39 years old, and over 40 years old are 15.4%, 17.2%, and 21.1%, respectively. [14]

It should be noted that only aneuploidy and DFI are discussed here. In addition, DNA mutations and epigenetic changes in older men will also affect the health of their offspring. Therefore, when older men have fertility needs, genetic evaluation of sperm is also necessary and is increasingly valued in clinical practice.

Summarize

It is true that compared with women, men can maintain their fertility for a longer time. By quitting smoking, drinking, living a regular life, exercising properly, and treating illnesses, physical condition can be maintained to a certain extent. However, aging is inevitable, and aging is an unchangeable fact. There are indeed examples of elderly men having children, but they are also accompanied by "probability" and "risk". With the development of assisted reproductive technology, elderly men can help conceive through in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI).

However, assisted reproductive technology cannot guarantee that all possible genetic abnormalities can be eliminated, and there are still many questions waiting to be answered. Again, in addition to pre-pregnancy consultation and related medical tests before preparing for childbirth, the best way is to "do the right thing at the right time."

References

[1] Editor-in-Chief: Guo Yinglu, Xin Zhongcheng, Jin Jie. Male Reproductive Medicine (2nd Edition). Peking University Medical Press. 2016.

[2] Helena E Virtanen, Niel Jorgensen, Jorma Toppari. Nat Rev Urol. 2017; 14(2): 120-130.

[3] Gu Yiqun et al., translated. World Health Organization Laboratory Manual for the Examination and Processing of Human Semen (Fifth Edition). People's Medical Publishing House. 2011)

[4] Chuan Huang, Baishun Li, Kongrong Xu, et al. Fertil Steril. 2017; 107(1): 83-88.

[5] Nadia A du Fosse, Marie-Louise P van der Hoorn, Jan MM van Lith, et al. Hum Reprod Update. 2020; 26(5): 650-669.

[6] Yash S Khandwala, Valerie L Baker, Gary M Shaw, et al. BMJ. 2018; 363: k4372.

[7] Reichenberg A, Gross R, Weiser M, et al. Arch Gen Psychiatry. 2006; 63(9): 1026-1032.

[8] Buizer-Voskamp JE, Laan W, Staal WG, et al. Schizophr Res. 2011; 129(2-3): 128-32.

[9] Shi Qinghua, Xu Bo, Yang Qingling, et al. Journal of University of Science and Technology of China. 2008; 38(8): 883-889

[10] Sergerie M, G Laforest, L Bujan, et al. Hum Reprod. 2005; 20(12): 3446-3451

[11] Oya Sena Aydos, Yunus Yukselten, Fuat Kaplan, et al. Turk J Urol. 2015; 41(4): 191-197

[12] Liu Chengjun, Wang Aiming, Shang Wei, et al. Chinese Journal of Andrology. 2011;17(7):619-621.

[13] 2Sergey I Moskovtsev, Jennifer Willis, J Brendan M Mullen. Fertil Steril. 2006; 85(2): 496-9.

[14] Mie Zhaoyan, Wu Haifeng, Zhang Na, et al. Chinese Journal of Family Planning. 2012;20(1):30-36.