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The Risks of Advanced Paternal Age

The Risks of Advanced Paternal Age

This specific post focuses on The Risks of Advanced Paternal Age. This field of research still requires a lot more work and there is a lot that is unknown to scientists right now.

Recent research indicates that Risks of Advanced Paternal Age is significantly correlated with first trimester miscarriage.

Ten studies so far have addressed the theory that advanced paternal age contributes to the incidence of spontaneous miscarriage following natural or ART conception. These studies were included in the meta-analysis because their link between paternal age and spontaneous miscarriage was adjusted for maternal age in order to negate the co-linearity between paternal and maternal age.

However, these studies did not use the same definition of miscarriage with regard to gestational age, prompting the authors to perform two separate analyses putting the threshold for spontaneous fetal demise first at 20 weeks (nine studies) and then at 13 weeks (four studies) of pregnancy. Thus, fathers between 40-44 years of age were 23% more likely to contribute to the incidence of spontaneous miscarriage before 20 weeks of gestation than their younger peers. Similarly, when The Risks of Advanced Paternal Age were over 45 years the risk for pregnancy loss before 20 weeks was increased by 43% and before 13 weeks by 74%. 

Link to: https://www.focusonreproduction.eu/article/News-in-Reproduction-Miscarriage-2

Defects in the development of the skull, limbs, and heart is also another risk of paternal age over 40. Lastly, another possibility is the child developing autism, schizophrenia, and child acute lymphoblastic leukemia. It is believed that many of these conditions may be the result of genetic mutations in the sperm as a result of old age. If you are considering having a child above the age of 40, consult your physician and strategize with them so they can help guide you on your fertility journey. ⁠

Sperm Preparation for ART

When sperm is ejaculated it is surrounded by fluid. A typical ejaculate contains cells, debris, dead and damaged sperm, and healthy, motile sperm. Healthy sperm is critical to the success of ART procedures and so we use sperm preparation techniques to separate functional spermatozoa for IUI, IVF, and ART and for cryopreservation. In the IVF lab there are essentially 4 techniques we use commonly; Swim-up, Swim-down, Sucrose and Ficoll-400 density gradient techniques. Each lab finds that one of these techniques will yield more motile, live and normal looking sperm for their procedures. 

Companies like ZyMot sell specialty devices for sperm separation that can be very expensive. The idea is that they simulate the cervical and uterine pathways that sperm must navigate to naturally fertilize an egg. By mimicking this natural selection method, sperm can be isolated without the use of chemicals or centrifugation that may damage the sperm. Instead they use microfluidic technology to isolate healthy sperm by laminar flow, which creates gradients through channels. These devices have been tested in randomized controlled trials, which is the gold standard of medical research.  

Data shows that up to 25% of semen specimens from men with an undetectable burden of viral RNA (HIV particles in their blood) are HIV positive. Each semen sample must be tested because those results are not consistent. HIV is detected in some samples and not others form the same man, even when HIV is not detected in the blood. SPAR stands for special program of assisted reproduction. They have developed highly sensitive techniques to detect the viral load in semen samples viruses like HIV, CMV, and Hepatitis C, and special procedures to wash the semen samples. This allows the sperm to be used for IVF to decrease or virtually eliminate the risk of transmitting the infection. These specimens can only be used for IVF, they are not appropriate for intrauterine insemination. 

ICSI and PICSI, What are they? 

Before a man’s sperm can fertilize a woman’s egg, the head of the sperm must attach to the outside of the egg. Once attached, the sperm pushes through the outer layer to the inside of the egg (cytoplasm), where fertilization takes place.

Sometimes the sperm cannot penetrate the outer layer, for a variety of reasons. The egg’s outer layer may be thick or hard to penetrate or the sperm may be unable to swim. In these cases, a procedure called intracytoplasmic sperm injection (ICSI) can be done along with in vitro fertilization (IVF) to help fertilize the egg. During ICSI, a single sperm is injected directly into the cytoplasm of the egg.

Why would I need ICSI?

ICSI helps to overcome fertility problems, such as:

-The male partner produces too few sperm to do artificial insemination (intrauterine insemination [IUI]) or IVF.

-The sperm may not move in a normal fashion.

-The sperm may have trouble attaching to the egg.

-A blockage in the male reproductive tract may keep sperm from getting out.

-Eggs that did not fertilize by traditional IVF, regardless of the condition of the sperm.

In vitro matured eggs are being used.

-Previously frozen eggs are being used.

Will ICSI work?

ICSI fertilizes 50% to 80% of eggs. But the following problems may occur during or after the ICSI process:

Some or all of the eggs may be damaged.

The egg might not grow into an embryo even after it is injected with sperm.

The embryo may stop growing.

Once fertilization takes place, a couple’s chance of giving birth to a single baby, twins, or triplets is the same if they have IVF with or without ICSI.

ICSI was developed for men with poor sperm quality and quantity. Low sperm count, sperm motility, and abnormal morphology can be indications for ICSI. Abnormal morphology (shape of sperm) has been linked to poor fertilization. Fertilization can now be achieved for men where it previously seemed impossible. It is now used exclusively in some clinics, and it is especially important for couples who want to have their embryos genetically tested. One of the reasons why it is so widely used now, is so that the embryologists can look at the eggs and know the quality and maturation right after the egg retrieval. In conventional IVF, the egg quality and maturity is essentially a mystery because the eggs are surrounded by cells until the day after the fertilization. Fertilization rates are generally higher after ICSI compared to conventional IVF. The more embryos you have the better the chance of pregnancy!

One variation of ICSI is called “PICSI” which stands for physiological ICSI, and uses a specialized dish coated in a substance called hyaluronan.  Healthy sperm are attracted to that enzyme and stick to it, they are later used to inject the egg with. 

What if your IVF Lab does ICSI, But you want to try conventional IVF? 

It’s in your best interest to do what the clinic does 99% of the time and not try to be one successful person on a procedure they do 1% of the time. Clinics have switched to ICSI for very very good reasons. It increases our patients success rates. It decreases chances of contaminating DNA from sperm during PGT. The embryologist will be able to examine and inject the nicest looking sperm. Think about it this way, you are preparing for the “Olympics” of baby making. We want to do anything in our power to shave 1 second off your timing so you can WIN the gold. A take home baby as quickly as possible. 

Veering from the established standard of care for a lab (any lab) introduces another possibility to the mix; one of them making an error. 

Why are you hesitating? Some people want it to be as natural as possible, but that’s not a good reason. Everything about the lab environment is not natural. Yes, fertilization failures do happen. This is not the thing to leave to chance, as you will get more than enough of that after the embryo is transferred back to your uterus. Allow the lab to do the procedures that give the highest success rates.

Freeze all Vs. Fresh Transfer

A suggestion originated in the early 2000s that the high hormone levels derived from a stimulated IVF cycle would encourage a non-receptive, out-of-phase endometrium, the concept arose that adopting a freeze-all approach would not only minimize the risk of ovarian hyper response syndrome, but maybe even improve pregnancy rates in the general IVF population.

The latest clinical meta-analysis of fresh vs frozen transfers, now involving 5379 eligible subjects and 11 trials, found eFET associated with a higher live birth rate only in hyper-responders. There was no outcome difference between fresh and frozen in normal responders, nor in the cumulative live birth rate of the two overall groups. Now, here is where it gets complicated. 

The CDC described the increase in the number of elective FET cycles between 2007 and 2016 as ‘dramatic’, rising steeply from almost zero to more than 60,000 cycles per year. In its summary of US activity for 2016 the CDC seems unequivocal – at least, based on its observational registry data – that rates of pregnancy and live birth are higher after frozen transfers than after fresh. Yet the (published, peer reviewed or randomized clinical trial) so far has not shown a large difference. It seems to be a case where the clinical trials have not caught up with clinical practice, and because there is clear evidence that for hyper responders outcomes are better, many clinics are now relying on a freeze all strategy to reduce this poor outcome. 

Endometrial Receptivity Assays 

The endometrium must be prepared with progesterone for the embryo to implant. The typical metric is to look for a thick “triple line” pattern. ERA testing determines if the endometrium is “genetically” receptive or not at the time of sampling, by analyzing a few hundred genes that get turned on or off and are known to be important for true endometrial receptivity. When your lining looks ready after but is not expressing the right genes and therefore the right proteins, your “window of implantation” is displaced. ERA testing can find your personalized window of implantation in case of displacement, and will allow a personalized timing for embryo transfer. 3 in every 10 patients have a displaced window of implantation. Use of the ERA test in one study, resulted in a 73% pregnancy rate in patients with previous implantation failure.


Oocyte Activation 

A small percentage of individuals continue to face repeated fertilization failure, even with normal sperm parameters and a good ovarian response and multiple ICSIs. Normally, when the sperm binds an egg a cascade of events occurs that results in oscillating waves of calcium ions in the egg. This is called egg activation! If this is missing or deficient in a patient it results in zygotes that arrest and cleavage stage defects. Calcium ionophores are the molecules that increase the concentration of calcium ions, and when artificially applied to an egg can activate the egg so that fertilization can occur.

A meta-analysis by Murugesu et al. (2017) included fourteen studies, and found activation with calcium ionophore increased fertilization, embryo cleavage, blastocyst and implantation rates, as well as overall clinical pregnancy rate per embryo transfer (OR=3.48) and live birth rate (OR=3.44). Calcium ionophore treatment may be especially helpful for patients with specific conditions, such as a condition called globozoospermia, which is when the sperm lacks a feature called the acrosome, or if previous, unexplained failed fertilization occurred.


In vitro gametogenesis (IVG)

A new process called in vitro gametogenesis (IVG) is currently being developed, and if successful, it will completely transform the way humans think about reproduction.

The process of IVG creates sperm and egg cells in a lab from just about any adult cell. IVG uses skin or blood cells to reverse engineer a special type of cells called induced pluripotent stem cells (iPSCs). Essentially, iPSCs are adult cells that have been genetically reprogrammed into an embryonic state, meaning they have the potential to transform into any type of cell: kidney cells, muscle tissue, sperm, or eggs.

IPSCs can be used to create the necessary components for reproduction: eggs and sperm. They’re also at the forefront of all sorts of important research, including disease treatment, transplant science, and cutting-edge drug development.

In the hypothetical human IVG process, an individual would provide a skin biopsy. A lab would then reprogram those skin cells to create induced pluripotent stem cells, which would then be used to create eggs or sperm.

Today, we still need a man and a woman to make a baby. Reproduction still requires testes to make sperm and ovaries to produce eggs. 

In 2016, a team of scientists at Tokyo University of Agriculture in Japan helped a female mouse successfully give birth to 26 pups, using eggs created from skin cells.

In 2018, Japanese scientists were able to generate immature human eggs, using induced pluripotent stem cells derived from human blood cells. These incomplete eggs would not be viable for fertilization, but they do represent a major step toward the development of a successful human IVG process.

DHEA – de hydro epiandrosterone. 

One of the hottest topics in IVF right now is the use of DHEA to rejuvenate ovarian function, because currently up to 1 in 4 IVF cycles are characterized by poor ovarian response. “Poor responders” suffer from Diminished Ovarian Reserve (DOR) resulting in fewer oocytes and decreased rates of pregnancy. Some studies claim that use of DHEA supplementation improves pregnancy chances in women with Diminished Ovarian Reserve by reducing aneuploidy—chromosome number abnormalities in embryos. DHEA, according to some reports, has been very successful in increasing the number and quality of eggs, reducing the risks of miscarriages and shortening the time to pregnancy. 

Vitamins and Infertility 

It’s our vitamins and fertility post: ALL. THINGS. VITAMINS.

Find out why certain vitamins are essential in maintaining fertility and sources where you can find these vitamins to incorporate into your diet.

Vitamin A

Vitamin A is crucial for the functioning of various body systems and organs. One of these systems is the reproductive system.

Spermatogenesis  is quite dependent on vitamin a. It is what helps keep structures such as the epididymis and seminal vesicle functioning. without it, instead of finding those structures you might find “stratified squamous keratinizing epithelium.”

In females the problems could be found in ovulation. A study on vitamin A deficient rats showed that the rats were unable to ovulate and form corpora lutea routinely. researchers were also not able to see blastogenesis occur. vitamin A could play a crucial role even after fertilization! it has been shown that a mother’s vitamin A keeps the placenta in good condition.

In studies performed on pigs, it was observed that a lack of vitamin A resulted in several birth defects including cleft palate, lack of eye development etc. embryos observed during days 12.5-20.5 demonstrated a range of defects in vision related structures such as the retina and iris.

The nervous system also uses vitamin a for functions such as neural differentiation. vitamin a deficient (vad) quail embryos have been seen to have underdeveloped hindbrains. they also did not have many spinal cord neurons. Some other problems were observed in vad rat embryos. these included:

  • impaired heart morphogenesis
  • non-compartmentalized heart
  • embryonic renal hypoplasia
  • impaired diaphragm development.
  • bilateral lung hypoplasia

There are many more conditions that can develop in embryos. however, making sure that you include sufficient amounts of vitamin A in your diet prevents such birth defects. it is important to keep in mind that eating healthy is very important during early pregnancy and even pre-pregnancy. It is often stressed to get your vitamins from food rather than supplements. vitamin a can be found in variety of foods including:

  • green leafy vegetables
  • dairy products.
  • carrots
  • sweet potatoes, tomatoes
  • red bell peppers
  • squash and pumpkin
  • essentially any orange colored food!


1. Clagett-Dame et al. “Vitamin A in Reproduction and Development” Nutrients. Mar 29 2011

2. “Vitamin A” Harvard T.H. Chan School of Public Health

Vitamin D

Scientists are still not completely sure whether vitamin d deficiency is associated with IVF outcomes. The authors of a study did conclude, however, that vitamin D does not affect pregnancy, live birth, and miscarriage rates. They were also able to find reason to believe vitamin D is involved in folliculogenesis, oogenesis and endometrial receptivity. Studies are split between whether vitamin D deficiency is a serious issue for individuals who plan on using art. certain fertility clinics screen patients for vitamin d deficiency prior to beginning treatment.

A good level of vitamin D for fertility treatments is often considered to be 30 ng/ml. It is important to be able to maintain this level even throughout a pregnancy as studies have shown vitamin D deficiency may induce preeclampsia, gestational diabetes, and other conditions. The reason for this may be that vitamin D is known to be involved in the embryo implantation process. It controls the genes that generate estrogen and also helps to shift around immune cells in the uterus to fight off infections. Some good sources of vitamin D include:

  • oily fish
  • red meat
  • liver
  • egg yolks
  • supplements (because it can sometimes be difficult to get sufficient amounts from diet and sunshine). We recommend the BlueBonnet brand available on Amazon.


Vitamin E 

Researchers from another study were able to determine an association between recurring abortion and low plasma vitamin e levels and increased lipid peroxidation levels in women. Regarding fetus/embryo growth, it’s important to bring up the study of in vitro matured and fertilized bovine oocytes. The zygotes derived from them when cultured in vitamin E, vitamin C, and edta were more likely to enter the blastocyst stage than the control medium.

Current studies indicate there is still more we need to know about vitamin E! The University of Rochester is currently conducting trials involving 48 infertile men and 20 fertile men on how vitamin E affects sperm fragmentation. DNA fragmentation occurs due to oxidative stress. because vitamin E is an antioxidant, it can combat such oxidative stress. It leaves us questioning if vitamin E deficiency perhaps leads to DNA fragmentation? Want to try and incorporate more vitamin E into your diet? Here’s some foods that Healthline listed which you should eat!

  • Sunflower seeds
  • Almonds
  • Sunflower oil
  • Hazelnuts (I’m going to go eat that Ferrer Rocher now!)
  • Pine nuts
  • Peanuts
  • Avocado
  • Brazil nuts
  • Kiwi


1. Mutalip et al. “Vitamin E as an Antioxidant in Female Reprosuctive Health” Antioxidants. Feb 2018. 

2. Vitamin E and Male Fertility study on ClinicalTrials.gov

3. Olson et al. “Culture of in vitro-produced bovine embryos with Vitamin E improves development in vitro and after transfer to recipients.” Biol Reproduction. Feb 2000.