As I understand it, mutations quite often lead to an embryo not making it to birth. So if a woman has a miscarriage, what are the odds that a mutation caused it?
Its impossible to test for minor mutations, apart from specific diseases.
BUT Trisomy 18 is one common haplotype problem that results in definite pregnancies , even to third trimester but not live births. And if born, a high % die.
T18 is more common than downs, T21, but the foetus survives less often, in absolute terms, and so downs syndrome results in children born and living with the defect… that makes them famous.
From Types of Trisomy: Causes and Symptoms
Trisomy of 15, 16, 22 ,and 23 also cause miscarriages.
Presumably trisomy of other chromosomes doesn’t lead to a detectable miscarriage.
I guess it depends what you mean by “misscarriage”. Most nonviable pregnancies have chromosome abnormalities. All trisomies except 21, 18, and 13 are incompatible with life.
Our ability to detect pregnancy at a very early stage has improved. And this has resulted in the realization that more pregnancies are lost in those early weeks due to genetic errors. Fifty years ago such a pregnancy might not have been recognized and a woman might think her cycle was a couple days late.
Miscarriage occurs in about 15-20% of all recognized pregnancies. Include the very early miscarriages where the pregnancy may not have been recognized and the March of Dimes estimates that up to 40% of all pregnancies end in miscarriage. (Amazing we manage to continue as a species with that kind of failure rate!)
More than 50% of first trimester miscarriages are the result of chromosomal problems in the fetus. In women with repeated pregnancy loss, about 70% of their miscarriages may be related to genetic errors.
Chromosomal problems could include an extra or missing chromosome (aneuploidy), chromosomes with missing pieces (deletions), chromosomes where pieces of different chromosomes have become stuck together (translocations), or chromosomes where pieces broke and were spliced back in backwards (inversions). Aneuploidy is the most likely of these to result in miscarriage and increases in frequency with parental age.
A simple Single-Nucleotide Polymorphism, where one “letter” in the genetic code is incorrectly copied and substituted with another is not very likely to prove fatal to the fetus.
Wonderful post, Iggy! Thank you!
Bolding mine.
I just wanted to add that there are additional factors that are not well understood that may cause repeated miscarriage, such as immune issues. There is a growing body of knowledge that shows that immune issues, such as NK Cell activity, can also cause early miscarriage. There is a lot more research needed, but I would guess that maybe half of the losses occurring in RPL patients is related to the mothers immune system, not genetic abnormalities in the fetus.
The numbers Iggy cited were obtained by looking directly at the abortuses themselves. It’s unlikely that they will turn out to be THAT far off.
This is just what I was wanting to know. I knew it happened but I wasn’t sure if it was a common reason for miscarriage or if it was rare. So major genetic anomalies are a very common reason while minor mutations are pretty rarely a cause. (If I recall correctly, a lot of our DNA isn’t even active so a minor mutation might have no effect whatsoever.)
To ask a technical question, would the term “mutation” typically be used for all of those by people working in the field? (On the Wikipedia pages linked, one of them uses word mutation, one has the word only appear in the titles to the references, and two don’t have the word at all.)
Also, could some of those have occurred in the fetus’s parents or earlier ancestors and been passed along, or would they all have occurred in the sperm and egg production?
The term “mutation” would be the broad category term for unrepaired changes in the genetic code. In a discussion of reproduction “mutation” generally refers to newly arisen changes rather than something passed down from prior generation(s). So the term “mutation” could be used, but geneticists are prone to jargon as much as any technical field and may tend to use the term for the exact type of genetic change, if known.
If the mutation proved immediately fatal in the fetus then obviously it would not be passed down. But not all structural changes to chromosomes are fatal. Balanced translocations may be present in a healthy adult but yet result in fertility problems due to unbalanced translocations in the gametes due to recombination. This would be a type of structural chromosomal abnormality which could be inherited over a series of generations.
Another type of non-fatal change is an aneuploidy due to a Robertsonian translocations. This basically results in two chromosomes being fused together with minimal loss of genetic material*. A person might only have 45 chromosomes, but have few deficits due to having all the necessary DNA (just that the DNA is wrapped up in fewer packages). Still this could result in infertility problems due to an imbalance of genetic material in the gamete.
On average, each of us carry about 65 new single-nucleotide polymorphisms. Those are single base pair substitutions which were not present in a parent. Most of those will fall into non-coding portions of our genome and have absolutely no effect. Of those within coding portions of the genome about 40% or so will still have no effect due to redundancy within how the genetic code is transcribed.
*Cool footnote. Fusing of two chromosomes in that way seems to have happened in the evolution of humans. Neanderthals and earlier Hominids had 24 pairs of chromosomes. Two of those fused to form our chromosome #2, leaving humans with only 23 pairs of chromosomes.
I am referring to early miscarriages (<6 weeks), where there would be no fetus to test.
So am I. As Iggy said, we can now detect those very early miscarriages and examine the aborted tissue.
Just because we can detect those early miscarriages doesn’t mean we have the tissue to examine. For a lot of women miscarrying that early, the main symptom is menstruation-like bleeding – and by the time you realize what’s happening, what little tissue had been present is probably already out and/or gone. You’re certainly not going to bring your bloodied clothes and toilet paper to the doctor to be examined for remains.
Disclaimer: I am not an Ob/Gyn, just someone who miscarried at 5 and 6 weeks.
Rhesus incompatibility would be the classic example for that.
That failure rate is actually one of the reasons we can continue on as a species. Ending a pregnancy when the baby will be disabled/not-viable saves resources and helps ensure genetic healthiness.
Normally, of course, no, people don’t collect the tissue to study. But studies have been done to look specifically at these early miscarriages.
Because the zygote/embryo and half the placenta, umbilical cord and sac all develop from the same single fertilized cell, we don’t necessarily need to find the zygote itself to run DNA testing that can indicate a chromosomal abnormality was/would have been present. You can test what’s on the pad a couple of days into the miscarriage. Theoretically, anyhow. I’m not sure how they actually collect the samples for testing.
But yes, I agree - unless you’re holding a random representative sample of women in observation for 10 weeks after they have sex, I think you’re still going to miss a whole lot of those very early miscarriages, because few people report a slightly late, heavier than normal “period”.
This link shows the estimated percentages of loss due to various issues: Reproductive Immunology Associates, though it doesn’t indicate studies to back it up. Their estimated rate for immune issues is up to about 50%. Of those, about 90% are autoimmunewhile 10% are alloimmune.
How about later miscarriages? I miscarried at 18 weeks in the 1970s, and AFAIK no effort was made to find out why. I asked the doctor and got no answer. I’d had a successful pregnancy a couple of years before, and had another about a year later; however in both those cases I took a drug to increase ovulation. I believe the drug was Clomid. I’ve often wondered if it was significant that the miscarriage was the pregnancy that was not preceded by a fertility drug.
If anyone’s interested, I just moments ago attended a seminar by a Harvard professor who is studying meiosis. The numbers she cited were 20% of preimplantation embryos and 35% of implanted embryos having some sort of chromosomal abnormality. She didn’t have a reference on the slide, so I don’t know where those numbers came from.